WO2008133766A1 - Blocking the migration or metastasis of cancer cells by affecting adhesion proteins and the uses of new compounds thereof - Google Patents
Blocking the migration or metastasis of cancer cells by affecting adhesion proteins and the uses of new compounds thereof Download PDFInfo
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- WO2008133766A1 WO2008133766A1 PCT/US2008/002086 US2008002086W WO2008133766A1 WO 2008133766 A1 WO2008133766 A1 WO 2008133766A1 US 2008002086 W US2008002086 W US 2008002086W WO 2008133766 A1 WO2008133766 A1 WO 2008133766A1
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- cancer
- angiopoietin
- benzoyl
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Definitions
- This invention provides methods and compositions for affecting the gene expression in cells as a result that cure diseases, wherein the methods comprise reducing the syndrome of diseases.
- the methods comprise inhibition of gene expression.
- the method comprises stimulating the gene expression.
- This invention provides methods, processes, compounds and compositions for modulating the gene expression or secretion of adhesion proteins or their receptors to cure disease, wherein the modulating comprises positive and negative regulating; wherein comprises inhibiting cancer growth, wherein the adhesion proteins or receptors comprise fibronectin, integrins family, Myosin , vitronectin, collagen, laminin, Glycosylation cell surface proteins, polyglycans, cadherin, heparin, tenascin, CD 54, CAM, elastin and FAK.
- Metastasis is the late stage of cancer in which cancer cells leave the original tumor site and migrate to other parts of the body.
- the cancer cells break away from the primary tumor and attach to the surrounding extracellular matrix and migrate to other parts of the body via bloodstream or the lymphatic system.
- the adhesion protein play an essential role in cancer metastasis.
- This invention provides a method of modulating the adhesion of cancer cell and block their migration, metastasis or inhibit the growth of cancers or anti-angiogenesis, wherein the adhesion protein and their receptors comprise fibronectin, integrins family, Myosin , vitronectin, collagen, laminin, Glycosylation cell surface proteins, polyglycans, cadherin, heparin, tenascin, CD 54, CAM, elastin and FAK.
- This invention provides a method of reducing the adhesion protein in cell and block the migration, metastasis of cancer cells or inhibit the growth of cancers or anti- angiogenesis, wherein the adhesion proteins or its receptors comprise fibronectin, integrins family, Myosin, vitronectin, collagen, laminin, Glycosylation cell surface proteins, polyglycans, cadherin, heparin, tenascin, CD 54, CAM, elastin and FAK.
- this invention provides a method of reducing the secretion of fibronectin.
- this invention provides a method for inhibiting the expression of adhesion proteins, wherein the adhesion proteins comprise fibronectin, integrins family, Myosin , vitronectin, collagen, laminin, Glycosylation cell surface proteins, polyglycans, cadherin, heparin, tenascin, CD 54, CAM, elastin and FAK.
- adhesion proteins comprise fibronectin, integrins family, Myosin , vitronectin, collagen, laminin, Glycosylation cell surface proteins, polyglycans, cadherin, heparin, tenascin, CD 54, CAM, elastin and FAK.
- This invention provides a method of inhibiting the growth, migration, metastasis of cancer by altering the characteristics of membrane of cancer cells, wherein the characteristics comprise adhesion protein; wherein the cancers comprise breast, leukocyte, liver, ovarian, bladder, prostate, skin, bone, brain, leukemia, lung, colon, CNS 1 melanoma, renal and cervix cancer.
- FIG. 1 Time studies of inhibition of Fibronectin secretion from cancer cells (ES2) after incubation of Xanifolia-Y. Fibronectin released in culture medium was determined byWestern blot A: (results of experiment F1) Y is Xanifolia compound Y; B: (results of experiment F3); C: (results of experiment F4)
- Figure 2 Inhibition of Fibronectin Secretion by Xanifolia-Y (Western Blot).
- Figure 3 Inhibition of Fibronectin Secretion by Xanifolia-Y (Western Blot).
- Figure 4 Inhibition of Fibronectin Secretion by Xanifolia-Y (Western Blot).
- Figure 5 Increase synthesis of Angiopoietin-2 in ES2 cells by Xanifolia-Y treatment.
- This invention provides methods and compositions for modulating the gene expression to cure diseases or reduce the syndrome of diseases, wherein the modulating comprises positive and negative regulating.
- the method comprises inhibiting the gene expression.
- the method comprises stimulating the gene expression.
- This invention provides methods and compositions for inhibiting the migration, metastasis or growth of cancers or anti-angiogenesis, wherein the methods comprise affecting the gene expression, wherein comprise affecting the adhesion proteins or their receptors, reducing adhesion protien, or inhibiting the expression or secretion of adhesion proteins, wherein the adhesion proteins comprise fibronectin, integrins family, Myosin , vitronectin, collagen, laminin, Glycosylation cell surface proteins, polyglycans, cadherin, heparin, tenascin, CD 54, CAM, elastin and FAK.
- This invention provides methods and compositions for inhibiting the migration, metastasis or growth of cancers or anti-angiogenesis, wherein the methods comprise affecting the gene expression, wherein comprises stimulating the gene expression.
- This invention provides a method for altering the characteristic of cancer cell membrane resulting in blocking the migration, metastasis of cancer cells or inhibit the growth of cancers or anti-angiogenesis, wherein the method comprises reducing adhesion protiens or their receptors, wherein the adhesion proteins comprise fibronectin, integrins family, Myosin , vitronectin, collagen, laminin, Glycosylation cell surface proteins, polyglycans, cadherin, heparin, tenascin, CD 54, CAM, elastin and FAK.
- This invention provides methods, processes, compounds and compositions of reducing adhesion protein of cells, wherein the adhesion proteins comprise fibronectin, integrins family, Myosin, vitronectin, collagen, laminin, Glycosylation cell surface proteins, polyglycans, cadherin, heparin, tenascin, CD 54, CAM, elastin and FAK.
- methods comprise inhibiting the gene expression.
- this invention provides a method of reducing the secretion of fibronectin.
- the method can block the migration, metastasis of cancer cells or inhibit the growth of cancers or anti-angiogenesis, wherein the cancers comprise breast cancer, leukocyte cancer, liver cancer, ovarian cancer, bladder cancer, prostate cancer, skin cancer, bone cancer, brain cancer, leukemia cancer, lung cancer, colon cancer, CNS cancer, melanoma cancer, renal cancer or cervix cancer,
- This invention provides a method of altering the characteristic of cancer cell membrane, wherein the method comprises altering the secretion of adhesion proteins, wherein the adhesion proteins comprise fibronectin, integrins family, Myosin, vitronectin, collagen, laminin, Glycosylation cell surface proteins, polyglycans, cadherin, heparin, tenascin, CD 54, CAM, elastin and FAK.
- the methods, processes, compounds and compositions comprises blocking, suppressing or inhibiting the expression or secretion of adhesion protein, wherein the adhesion proteins .
- the methods, processes, compounds and compositions is interacting with adhesion protein, wherein the adhesion proteins.
- the methods, processes, compounds or compositions can block the migration, metastasis of cancer cells or inhibit the growth of cancers or anti-angiogenesis, wherein the cancers comprise breast, leukocyte, liver, ovarian, bladder, prostate, skin, bone, brain, leukemia, lung, colon, CNS, melanoma, renal and cervix cancer.
- the adhesion proteins help cancer cell adhesion, invasion or metastasis, wherein the cancers comprise ovarian cancer. Reducing the adhesion proteins will reduces the metastasis of cancers.
- the fibronectin is one of the key factors in the biology of epithelial ovarian cancers. The reducing of fibronectin will inhibit the metastasis of cancer cells.
- This invention provides a method and composition for inhibiting the secretion of adhesion protein comprising fibronectin in order to cure the diseases, wherein the diseases comprise inhibiting cancer growth, wherein the cancers comprise breast, leukocyte, liver, ovarian, bladder, prostate, skin, bone, brain, leukemia, lung, colon, CNS, melanoma, renal and cervix cancer.
- This invention provides a composition for inhibiting the growth, migration, metastasis of cancer and by altering the characteristics of membrane of cancer cell, wherein the characteristics comprise adhesion of proteins; wherein comprising the secretion of proteins or the adhesion of cells; wherein the characteristic comprise adhesion ability; wherein the adhesion proteins comprise fibronectin, integrins family, Myosin , vitronectin, collagen, laminin, Glycosylation cell surface proteins, polyglycans, cadherin, heparin, tenascin, CD 54, CAM, elastin and FAK; wherein the cancers comprise breast cancer, leukocyte cancer, liver cancer, ovarian cancer, bladder cancer, prostate cancer, skin cancer, bone cancer, brain cancer, leukemia cancer, lung cancer, colon cancer, CNS cancer, melanoma cancer, renal cancer or cervix cancer; wherein the method is administering contacting XanifoliaYO, Y1, Y2, Y 1 Y7, Y8,
- This invention provides a method for altering the adhesion characteristic of membrane of cancer cell, wherein the method compring reducing the adhesion ability, wherein the method comprises reducing the secretion of fibronectin.
- the cancers comprise breast cancer, leukocyte cancer, liver cancer, ovarian cancer, bladder cancer, prostate cancer, skin cancer, bone cancer, brain cancer, leukemia cancer, lung cancer, colon cancer, CNS cancer, melanoma cancer, renal cancer or cervix cancer, wherein the method is administering contacting an effective amount of Xanifolia YO, Y1, Y2, Y, Y7, Y8, Y9, Y10, ACH-Y or a salt, ester, metabolite thereof.
- the method is administering contacting an effectie amount of the compound selected from formulas in this application. In an embodiment, the method is inhibiting the growth, migration, metastasis of cancer.
- the compound may be selected from formula (1A), (1B), (1C) and (1D).
- the compound comprises a triterpene backbone, two angeloyl groups and sugar moiety.
- the compound(s) are selected from Xanifolia (x), Escin or Aescin.
- the compound(s) are selected from Compound A to X and A1 to X1.
- the compound(s) are selected from Compound Z1 to Z7, in the application.
- This invention provides a composition for inhibiting the growth, migration, metastasis of cancer by altering the adhesion characteristic of membrane of cancer cell, wherein the cancers comprise breast cancer, leukocyte cancer, liver cancer, ovarian cancer, bladder cancer, prostate cancer, skin cancer, bone cancer, brain cancer, leukemia cancer, lung cancer, colon cancer, CNS cancer, melanoma cancer, renal cancer or cervix cancer.
- This invention provides a method and composition for reducing of adhesion protein to cure the diseases, wherein the diseases comprise inhibiting cancer growth, reducing leg swelling, symptoms of chronic venous insufficiency, peripheral edema, antilipemic, chronic venous disease, varicose vein disease, varicose syndrome, venous stasis, expectorant, peripheral vascular disorders, cerebro-organic convulsion, cerebral circulation disorder, cerebral edema, psychoses, dysmenorrhea!, hemorrhoids, episiotomies, peripheral edema formation or postoperative swelling; for reducing symptoms of leg pain; for treating pruritis, lower leg volume, for reducing symptoms of pain; thrombosis, thromophlebitis; for preventing gastric ulcers antispasmotic, comprising administering to a subject, in need thereof, an effective amount of the composition of this invention.
- the method comprises interacting with adhesion protien, wherein the adhesion proteins comprise fibronectin, integrins family, Myosin, vitronectin, collagen, laminin, Glycosylation cell surface proteins, polyglycans, cadherin, heparin, tenascin, CD 54, CAM, elastin and FAK.
- adhesion protien comprising fibronectin, integrins family, Myosin, vitronectin, collagen, laminin, Glycosylation cell surface proteins, polyglycans, cadherin, heparin, tenascin, CD 54, CAM, elastin and FAK.
- this invention provides a method of reducing the secretion of fibronectin.
- the method comprises reducing the adhesion ability of adhesion protein; wherein the adhesion proteins comprise fibronectin, integrins family, Myosin, vitronectin, collagen, laminin, Glycosylation cell surface proteins, polyglycans, cadherin, heparin, tenascin, CD 54, CAM, elastin and FAK.
- adhesion proteins comprise fibronectin, integrins family, Myosin, vitronectin, collagen, laminin, Glycosylation cell surface proteins, polyglycans, cadherin, heparin, tenascin, CD 54, CAM, elastin and FAK.
- the method comprises modulating the secretion of adhesion protien, wherein the adhesion proteins comprise fibronectin, integrins family, Myosin, vitronectin, collagen, laminin, Glycosylation cell surface proteins, polyglycans, cadherin, heparin, tenascin, CD 54, CAM, elastin and FAK.
- the method comprises blocking the secretion of adhesion protien, wherein the adhesion protein comprising fibronectin.
- the method is administering contacting an effective amount of the compound selected from formulas in this application.
- the method is administering contacting an effective amount of the compound in this application comprising Xanifolia YO, Y1, Y2, Y, Y7, Y8, Y9, Y10, ACH- Y, Xanifolia (x), Escin or Aescin or a salt, ester, metabolite thereof.
- the compound(s) are selected from Compound A to X and A1 to X1.
- the compound(s) are selected from Compound Z1 to Z7, in the application.
- the compound may be selected from formula (1A), (1B) 1 (1C) and (1D).
- This invention provides a method and composition for altering the characteristic of adhesion protein to cure diseases, wherein the characteristic comprising adhesion ability, wherein the method comprises reducing the secretion of fibronectin, wherein the diseases comprise inhibiting cancer growth, reducing leg swelling, symptoms of chronic venous insufficiency, peripheral edema, antilipemic, chronic venous disease, varicose vein disease, varicose syndrome, venous stasis, expectorant, peripheral vascular disorders, cerebro-organic convulsion, cerebral circulation disorder, cerebral edema, psychoses, dysmenorrhea!, hemorrhoids, episiotomies, peripheral edema formation or postoperative swelling; for reducing symptoms of leg pain; for treating pruritis, lower leg volume, for reducing symptoms of pain; thrombosis, thromophlebitis; for preventing gastric ulcers antispasmotic, comprising administering to a subject, in need thereof, an effective amount of the composition of this invention;
- R1 is selected from hydrogen, hydroxyl, O-angeloyl, O-tigloyl, O-senecioyl, O-alkyl, O- dibenzoyl, O-benzoyl, O-alkanoyl, O-alkenoyl, O-benzoyl alkyl substituted O-alkanoyl, O-aryl, O-acyl, O-heterocylic, O-heteroraryl, and derivatives thereof;
- R2 is selected from hydrogen, hydroxyl, O-angeloyl, O-tigloyl, O-senecioyl, O-alkyl, O- dibenzoyl, O-benzoyl, O-alkanoyl, O-alkenoyl, O-benzoyl alkyl substituted O-alkanoyl, O-aryl, O-acyl, O-heterocylic, O-heteroraryl, and derivatives thereof;
- R4 represents CH 2 R6 or COR6, wherein R6 is selected from a group consisting of hydroxyl, O-angeloyl, O-tigloyl, O-senecioyl, O-alkyl, O-dibenzoyl, O-benzoyl, O- alkanoyl, O-alkenoyl, O-benzoyl alkyl substituted O-alkanoyl, O-aryl, O-acyl, O- heterocylic, O-heteroraryl, and derivatives thereof; R3 is H or OH;
- R8 is H or OH, particularly OH
- R5 is a hydrogen or sugar moiety(ies), wherein the sugar moiety(ies) is/are selected from a group consisting of glucose, galactose, rhamnose, arabinose, xylose, fucose, allose, altrose, gulose, idose, lyxose, mannose, psicose, ribose, sorbose, tagatose, talose, fructose, alduronic acid, glucuronic acid, galacturonic acid, and derivatives or combination thereof; wherein R9, R10, R11, R12, R13, R14, R15 are independently attached a group selecting from CH 3 , CH 2 OH 1 CHO 1 COOH 1 COO-alkyl, COO-aryl, COO-heterocyclic, COO-heteroaryl, CH 2 Oaryl, CH 2 O- heterocyclic, CH 2 O- heteroaryl, alkyls group, hydroxyl, acet
- R5 is/are sugar moiety(ies) selected from a group consisting of glucose, galactose, arabinose, alduronic acid, glucuronic acid, galacturonic acid, and a derivative or combination thereof;
- the method is administering contacting the compounds, wherein the compound is selected from the following: a) An isolated, purified or synthesized compound is having structure Xanifolia(Y),
- the method is administering contacting the compound, wherein the compound is selected from the following:
- the method is administering contacting the compound, wherein the compound is isolated, purified or synthesized having a structure selected from following formulas:
- R1, R2 are individually selected of an O-acetyl or O-angeloyl; wherein the R3, R4, R5, R6, R7 is hydrogen or hydroxyl
- the method is administering contacting the compound in this application comprising Xanifolia YO 1 Y1, Y2, Y, Y7, Y8, Y9, Y10, Xanifolia (x), Escin or
- the compound may be selected from formulas (1A), (1 B), (1C) and (1D).
- the compound comprises a triterpene backbone, two angeloyl groups and sugar moiety.
- the compound(s) are selected from Xanifolia (YO, Y1, Y2, Y, Y7, Y8, Y9, and Y10).
- the compound(s) are selected from Xanifolia (x), Escin or Aescin.
- the compound(s) are selected from Compound A to X and A1 to X1 in the application.
- the compound(s) are selected from Compound Z1 to Z7 in the application.
- the method is administering contacting the compound comprise of a triterpene wherein the carbon position 21, 21 has a unsaturated group and sugar moieties at carbon 3.
- compounds of this application reducing the adhesion ability inhibit bacteria in colonization and regulate tropism of cells.
- the composition comprises the bioactive compounds from natural plants or synthesis.
- the majority of the plants are from the Sapindaceae family, which has 140-150 genera with 1400-2000 species.
- the program is based on our purification methods and biological assays including the MTT assay See International Application No. PCT/US05/31900, filed September 7, 2005, U.S. Serial No. 11/289142, filed November 28, 2005, and U.S. Serial No. 11/131551 , filed May 17, 2005, the contents of which are incorporated herein by reference
- compositions comprising a triterpenoidal saponin.
- the saponin has triterpenoid, triterpenoidal or other sapogenin, one or more sugar moieties and two angeloyl groups, or at least two side groups selected from the following groups: angeloyl groups, tigloyl groups or senecioyl groups, wherein the side groups are attached to the sapogenin backbone at carbon 21 and 22.
- This invention further provides a composition
- a composition comprising the structures substituted with at least two side groups selected from angeloyl, tigloyl or senecioyl groups, wherein the side groups are attached to a triterpenoidal, triterpenoid, triterpenoidal or other sapongenin backbone.
- These structures are obtainable from the natural or synthesis.
- This invention provides a method of preparing the bioactive compounds, comprising the steps of: (a) Extracting roots, kernels, leaves, bark, stem, husks, seeds, seed shells or fruits of the plant, or combinations thereof with organic solvents such as ethanol or methanol to obtain an organic extract; (b) Collecting the organic extracts; (c) Refluxing the organic extract to obtain a second extract; (d) Removing the organic solvent from the second extract to obtain a third extract; (e) Drying and sterilizing the third extract to obtain a crude extract powder; (f) Fractionating the crude extract powder into fractions or components.
- organic solvents such as ethanol or methanol
- Fractionation may be achieved by HPLC and FPLC chromatography with silica gel, C18 or other equivalent solid phase materials; (g) Monitoring the fractionating, if using HPLC or FPLC, the absorption wavelength at 207nm to 500nm may be used; (h) Identifying the bioactive components of the crude extract; (i) Purifying one or more bioactive components of the crude extract with FPLC to obtain one or more fractions of the bioactive component; and (j) isolating the bioactive components with chromatographic techniques that employ preparative columns and HPLC.
- this invention provides the method of MTT Assay TEST PLATFORM to test the bioactivities of the saponins or other compounds.
- HTB-9 (bladder), HeLa-S3 (cervix), DU145 (prostate), H460 (lung), MCF-7 (breast), K562 (leukocytes), HCT116 (colon), HepG2 (liver), U2OS (bone), T98G (brain), SK- MEL-5 (Skin) and OVCAR-3 (ovary).
- the cells were grown in following culture media: HeLa-S3, DU145, MCF-7, Hep-G2 and T98G are in MEN (Earle's salts); HTB-9, H460, K562 and OVCAR-3 in RPMI-1640; HCT-116 and U2OS in McCoy-5A.
- MTT Assay Assays. The procedure for MTT assay followed the method described by Carmichael et al. (1987) with modifications.
- the cells were seeded into a 96-well plate at concentration of 10,000/well for HTB-9, HeLa, H460, HCT116, T98G and OVCAR-3), 15,000/well for DU 145, MCF-7, HepG2 and U2OS), and 40,000/well for K562 for 24 hours before drug-treatment. The cells were then exposed to the drugs for 48 hours (72 hours for HepG2 and U2OS, and 96 hours for MCF-7).
- % cell-growth (TD-TO / TC-TO) x 100(1), where TC or TD represents O.D. readings of control or drug-treated cells.
- LC cytotoxicity
- Micro Array Analysis of gene expression of ES2 cells after Y-treatment by Microarray
- the microarray experiments were done in studying the gene expression. Total number of 54676 genes has been studied.
- ES2 cells were seeded in a T-25 flask with 4.5 million cells per flask for 24 hours.
- Cell culture was replaced with fresh medium with xanifolia- Y (Y) or DMSO no-drug -control (D) for 24 hours.
- Y xanifolia- Y
- D DMSO no-drug -control
- RNA extraction, labeling, hybridization, and data analysis RNA was extracted from tumor cells using the Qiagen RNeasy Kit. RNA quality and quantity was checked by the Agilent BioAnalyzer and the NanoDrop ® ND-1000 spectrophotometer respectively before further manipulation. The first and second cDNA strands were synthesized from 20 ng of total RNA using the Affymetrix T7 oligo(dT) primer protocol and kit for the two- cycle amplificaton. To produce amplified biotin-labeled-cRNA, the cDNA was reverse transcribed by in vitro transcription using the MegaScript kit from Ambion.
- Affymetrix array (Affymetrix, Inc.Santa Clara, CA) is comprised of over 1 ,300,000 unique oligonucleotide features that represent greater than 38,500 well-substantiated human genes.
- the array was hybridized for 16 hours at 45°C with rotation at 60 rpm then washed and stained with a strepavidin, R- phycoerythrin conjugate stain on the Affymetrix Fluidicis Station 450. Signal amplification was done using biotinylated antistreptavidin.
- the arrays were scanned using the GeneChip ® 3000 confocal laser scanner with autoloader. The images were analyzed and quality control metrics recorded using Affymetrix GCOS software version 1.4. Lastly, the expression value for each gene was calculated using dChip PM-only model based or Plier algorithm.
- the raw p-values were adjusted by the Benjamnin-Hochberg method for false discovery rate (FDR) control to yield an adjusted p-value.
- Western blot is applied in this invention as a method to detect the specific proteins in treated and untreated cells with compounds in this invention, wherein the cells are breast, leukocyte, liver, ovarian, bladder, prostate, skin, bone, brain, leukemia, lung, colon, CNS, melanoma, renal and cervix cancer
- Cells targeted cells were grown in RPMI 1640 medium. 1.5 million cells were seeded in a T25 flask and grown for 24 hours before drug-treatment.
- Drug-treatment Cells cultures were replaced with fresh RPMI medium containing either 2.5 ul of DMSO (as control) [D]; or 10, 20, 30, 40, 80 ug/ml of tested compounds. After 24 hours, aliquot of culture medium was taken out for Fibronectin determination (Western blot method). Cell viability at 24 hours was determined by MTT assay. Cultures were replaced with RPMI medium (5 ml) with MTT and incubated for an hour. The formation of formazan was dissolved in 10 ml of DMSO and OD at 570nm was measured (MTT units).
- Western Blot Spent culture medium was mixed with SDS sample buffer, boiled for 3 minutes before loading to SDS gel.
- This invention provides a composition comprising an effective amount of triterpenoidal saponins named as Xanifolia Y1, Y2, Y, Y7, Y8, Y9, Y10, YO or their derivatives for modulating the adhesion protein, reducing adhesion protein or reducing the secretion of fibronectin, for treating chronic venous insufficiency, peripheral edema, antilipemic, chronic venous disease, varicose vein disease, varicose syndrome, venous stasis, expectorant, peripheral vascular disorders, cerebro-organic convulsion, cerebral circulation disorder, cerebral edema, psychoses, dysmenorrhea!, hemorrhoids, episiotomies, peripheral edema formation or postoperative swelling; for reducing symptoms of pain; for reducing symptoms of stomach pain; for reducing symptoms of leg pain; for treating pruritis, lower leg volume, thrombosis, thromophlebitis; for treating rheumatism
- the method is administering contacting the compound in this application comprising Xanifolia YO, Y1 , Y2, Y, Y7, Y8, Y9, Y10, Xanifolia (x), Escin or Aescin or a salt, ester, metabolite thereof.
- the compound may be selected from formulas (1A), (1B), (1C) and (1D).
- the compound comprises a triterpene backbone, two angeloyl groups and sugar moiety.
- the compound(s) are selected from Compound A to X and A1 to X1 in the application.
- the compound(s) are selected from Compound Z1 to Z7 in the application.
- This invention provides a method for reducing adhesion proteins or their receptors on cells, wherein the adhesion proteins comprise fibronectin, integrins family, Myosin, vitronectin, collagen, laminin, Glycosylation cell surface proteins, polyglycans, cadherin, heparin, tenascin, CD 54, CAM, elastin and FAK.
- the method can block the migration, metastasis of cancer cells or inhibit the growth of cancers or anti- angiogenesis, wherein the cancers comprise breast cancer, leukocyte cancer, liver cancer, ovarian cancer, bladder cancer, prostate cancer, skin cancer, bone cancer, brain cancer, leukemia cancer, lung cancer, colon cancer, CNS cancer, melanoma cancer, renal cancer and cervix cancer.
- This invention provides a method for interacting with adhesion proteins or their receptors, wherein the adhesion proteins comprise fibronectin, integrins family, Myosin, vitronectin, collagen, laminin, Glycosylation cell surface proteins, polyglycans, cadherin, heparin, tenascin, CD 54, CAM, elastin and FAK.
- this invention provides a method of reducing the secretion of fibronectin.
- the method is blocking the migration, metastasis of cancer cells or treating a mammal cancers comprising administering to said mammal a therapeutically effective amount of a pharmaceutical composition comprising a composition comprises the molecular formula or compound in this invention.
- the cancers comprise Leukemia, Lung, Colon, CNS, Melanoma, Ovary, Renal, Prostate, Breast, bladder c, cervix, liver, bone , brain and Skin cancer.
- the compounds comprise Xanifolia YO, Y1 , Y2, Y, Y7.Y8, Y9, Y10, or a salt, ester, metabolite or derivative thereof.
- the compounds of this invention can be isolated from natural sources or synthesized.
- a salt of compound comprise sodium salt, potassium salt or calcium salt.
- This invention provides a method of modulating the adhesion proteins or their receptors, reducing the adhesion ability of the cancer cells, wherein the modulating comprises the positive or negative regulating.
- the adhesion proteins comprise fibronectin, integrins family, Myosin, vitronectin, collagen, laminin, Glycosylation cell surface proteins, polyglycans, cadherin, heparin, tenascin, CD 54, CAM, elastin and FAK.
- the method is reducing the secretion of fibronectin.
- This invention provides a method of blocking the migration, metastasis of cancer cells or inhibiting cancer cell growth comprising administering an effective amount of a pharmaceutical composition comprising a composition comprises the molecular formula or compound in this invention.
- the cancers comprise Leukemia cancer, Lung cancer, Colon cancer, CNS cancer, Melanoma cancer, ovarian cancer, renal cancer, Prostate cancer, Breast cancer, bladder cancer, cervix cancer, liver cancer, bone cancer, brain cancer and Skin cancer.
- the compounds of this invention can be isolated from natural sources or synthesized.
- the method is administering contacting the compounds, wherein the compound is selected from the following:
- This invention provides uses of a compound selected from a compound with formula (1B) 1 for modulating, regulating or interacting the adhesion protien, wherein the adhesion proteins comprise fibronectin, integrins family, Myosin , vitronectin, collagen, laminin, Glycosylation cell surface proteins, polyglycans, cadherin, heparin, tenascin, CD 54, CAM, elastin and FAK.
- this invention provides a method of reducing the secretion of fibronectin :
- R1 comprises a group selected from hydrogen, angeloyl, acetyl, tigloyl, senecioyl, alkyl, dibenzoyl, benzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, acyl, aryl, heterocylic, heteroraryl and derivatives thereof;
- R2 comprises a group selected from hydrogen, angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic, heteroraryl and derivative thereof;
- R4 represents CH 2 OR6 or COOR6, wherein R6 is selected from hydrogen, angeloyl, acetyl, acetyl, senecioyl,
- R1 comprises a sugar moiety wherein substituted with two groups selecting from angeloyl, acetyl, tigloyl, senecioyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic heteroraryl and a derivative thereof.
- R1 comprises a sugar moiety wherein substituted with at least one group selecting from angeloyl, acetyl, tigloyl, senecioyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic, heteroraryl and a derivative thereof.
- R2 comprises a sugar moiety wherein at least one group is selected from angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic, heteroraryl and a derivative thereof.
- R2 comprises a sugar moiety or a side chain wherein at least two groups are selected from angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic, heteroraryl and a derivative thereof.
- R4 comprises CH2OR6 or COOR6 wherein R6 is a sugar moiety which comprises at least one group selected from angeloyl, acetyl, tigloyl, senecioyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic, heteroraryl and a derivative thereof.
- R6 is a sugar moiety which comprises at least one group selected from angeloyl, acetyl, tigloyl, senecioyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic, heteroraryl and a derivative thereof.
- R4 comprises CH 2 OR6 orCOOR ⁇ , wherein R6 is a sugar moiety which comprises at least two groups selected from angeloyl, acetyl, tigloyl, senecioyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substitutedalkanoyl, aryl, acyl, heterocylic, heteroraryl and a derivative thereof.
- R6 is a sugar moiety which comprises at least two groups selected from angeloyl, acetyl, tigloyl, senecioyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substitutedalkanoyl, aryl, acyl, heterocylic, heteroraryl and a derivative thereof.
- R4 comprises CH2OR6 or COOR6, wherein R6 is a sugar moiety which comprises at least two groups selected from angeloyl, acetyl, tigloyl and senecioyl.
- R4 comprises CH 2 OR6 or COOR6 of formula (1B), at least two of R1 , R2 and R6 comprise the group selected from angeloyl, acetyl, tigloyl, senecioyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic, heteroraryl and a derivative thereof.
- R4 comprises CH 2 OR6 or COOR6 of formula (1B), at least two of R1 , R2 and R6 comprise angeloyl, benzoyl, alkenoyl, or a derivative thereof.
- R4 is a side chain comprising CH 2 OCOCH 3 , CH 2 COO-alkyl, CH 2 OH, COOH, angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic or heteroraryl or a derivative thereof.
- R5 comprises a sugar moiety, wherein the sugar moiety comprises one or more sugar of, but is not limited to glucose, galactose, rhamnose, arabinose, xylose, fucose, allose, altrose, gulose, idose, lyxose, mannose, psicose, ribose, sorbose, tagatose, talose, fructose, or alduronic acid: glucuronic acid, galacturonic acid, or derivatives thereof, or the combination thereof.
- R5 comprises a sugar moiety or a group capable of performing the function of the sugar moiety.
- the R5 represents H.
- R4 represents H, OH or CH 3 .
- position C23, C24, C25, C26, C29 and C30 of the compound independently comprise CH 3 , CH 2 OH, CHO, COOH, COOa-lkyl, COO-aryl, COO- heterocyclic, COO-heteroaryl, CH 2 Oaryl, CH 2 O- heterocyclic, CH 2 O- heteroaryl, alkyls group, acetyl group or derivatives thereof, particular CH3.
- R1 and R2 independently comprise an angeloyl group.
- R1 is a sugar moiety or a side chain which comprise two angeloyl groups.
- R1 and R2 independently comprise a benzoyl group.
- R1 is a sugar moiety which is substituted with two benzoly groups.
- R 3 represents H or OH.
- R8 may be OH
- substitution, deletion and/or addition of any group in the above-described compounds by other group(s) will be apparent to one of ordinary skill in the art based on the teachings of this application.
- substitution, deletion and/or addition of the group(s) in the compound of the invention does not substantially affect the biological function of the compound.
- a composition comprising an effective amount of the compound selected from the above formula or a salt, ester, metabolite or derivative thereof as a medicament for regulating or interacting with adhesion protien, wherein the adhesion proteins comprise fibronectin, integrins family, Myosin, vitronectin, collagen, laminin, Glycosylation cell surface proteins, polyglycans, cadherin, heparin, tenascin, CD 54, CAM, elastin and FAK.
- the adhesion proteins comprise fibronectin, integrins family, Myosin, vitronectin, collagen, laminin, Glycosylation cell surface proteins, polyglycans, cadherin, heparin, tenascin, CD 54, CAM, elastin and FAK.
- this invention provides a method of reducing the secretion of fibronectin; wherein the medicament is for inhibiting tumor or cancer cell growth and for treating cancer, wherein the cancers comprise breast cancer, leukocyte cancer, liver cancer, ovarian cancer, bladder cancer, prostate cancer, skin cancer, bone cancer, brain cancer, leukemia cancer, lung cancer, colon cancer, CNS cancer, melanoma cancer, renal cancer or cervix cancer.
- This invention provides uses of a compound selected from a compound of formula (1D), for regulating or interacting with adhesion protien, wherein the adhesion proteins comprise of fibronectin, integrins family, Myosin, vitronectin, collagen, laminin, Glycosylation cell surface proteins, polyglycans, cadherin, heparin, tenascin, CD 54, CAM, elastin and FAK.
- this invention provides a method of reducing the secretion of fibronectin. :
- R1 comprises a group selected from hydrogen, angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic, heteroraryl and a derivative thereof
- R2 comprises a group selected from hydrogen, angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic, heteroraryl and a derivative thereof
- R4 comprises CH 2 OR6 or COOR6, wherein R6 comprises a group selected from hydrogen, angeloyl, acetyl, t
- R7 is selected from CH 3 , CH 2 OH, COOH and COOalkyl. In an embodiment, R7 is selected from CH 3 , CH 2 OH, CHO, COOH, COOalkyl, COOaryl, COO-heterocyclic, COO-heteroaryl, CH 2 Oaryl, CH 2 O- heterocyclic, CH 2 O- heteroaryl, alkyls group, acetyl group and a derivative thereof.
- R1 represents a compound comprising a sugar moiety wherein the sugar moiety is substituted with at least two compounds selected from angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic , heteroraryl and a derivative thereof;
- R1 represents a compound comprising a sugar moiety substituted with at least one selected from angeloyl, acetyl, tigloyl, senecioyl, benzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic, heteroraryl and a derivative thereof;
- R2 represents a compound comprising a sugar moiety, wherein the sugar moiety substituted with at least one selected from angeloyl, acetyl, tigloyl, senecioyl, benzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic, heteroraryl and a derivative thereof;
- R2 represents a compound comprising a sugar moiety or a compound which substituted with at least two selected from, angeloyl, acetyl, tigloyl, senecioyl, benzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic, heteroraryl and a derivative thereof;
- R4 comprises a group selected from CH 2 OR6 and COOR6 wherein R6 is a sugar moiety which substituted with at least one selected from angeloyl, acetyl, tigloyl, senecioyl, benzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic, heteroraryl and a derivative thereof;
- R4 comprises a group selected from CH 2 OR6 and COOR6 wherein R6 is a sugar moiety which substituted with at least two selected from angeloyl, acetyl, tigloyl, senecioyl, benzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic, heteroraryl and a derivative thereof; In an embodiment, R4 comprises a group selected from CH 2 OR6 and COOR6 wherein R6 is a sugar moiety which substituted with at least two selected from angeloyl, acetyl, tigloyl and senecioyl.
- R4 comprises a group selected from CH 2 OR6 and COOR6 wherein R6 is a sugar moiety which substituted with at least two selected from angeloyl, acetyl, tigloyl, senecioyl, benzoyl, alkanoyl, alkenoyl, dibenzoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic, heteroraryl and a derivative thereof;
- R4 comprises a group seleced from CH 2 OR6 and COOR6 wherein at least two of R1, R2 and R6 comprise a group selected from angeloyl, acetyl, tigloyl, senecioyl, benzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic , heteroraryl and derivative thereof;
- R4 comprises a group selected from CH 2 OCOCH3, CH 2 COOalkyl, CH 2 OH, COOH 1 angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic, heteroraryl and derivative thereof.
- R5 comprises a sugar moiety, glucose, galactose, rhamnose, arabinose, xylose, fucose, allose, altrose, gulose, idose, lyxose, mannose, psicose, ribose, sorbose, tagatose, talose, fructose, alduronic acid, glucuronic acid or galacturonic acid, or derivative thereof, or the combination thereof.
- R5 comprises a compound capable of performing the function of the sugar moiety.
- the R5 comprises a H.
- R4 represents H or OH or CH 3 .
- position 24 of the compound is CH 3 or CH 2 OH
- positions 23, 24, 25, 26, 29, 30 of the compound independently comprise
- R5 comprises a sugar moiety comprising L-glucose, D-galactose, L- rhamnose, or/and L-arabinose.
- R1 and R2 independently comprise an angeloyl group; In a embodiment, R1 is a sugar moiety or rhamnose which comprise two angeloyl groups.
- R3 represents H or OH; In a further embodiment, the compounds canbe isolated from natural sources or synthesized.
- a sugar moiety is a segment of a molecule comprising one or more sugar groups.
- substitution, deletion and/or addition of any group in the above-described compounds will be apparent to one of ordinary skill in the art based on the teaching of this application.
- substitution, deletion and/or addition of the group(s) in the compound of the invention does not substantially affect the biological function of the compound.
- the method is regulating or interacting with adhesion protien, wherein the adhesion proteins comprise fibronectin, integrins family, Myosin, vitronectin, collagen, laminin, Glycosylation cell surface proteins, polyglycans, cadherin, heparin, tenascin, CD 54, CAM, elastin and FAK.
- the method is reducing the secretion of fibronectin.
- This invention provides a method for inhibiting the growth, migration, metastasis of cancer by altering the characteristic of membrane of cancer cell, wherein the characteristic comprise reducing adhesion protein; wherein the adhesion proteins comprise fibronectin, integrins family, Myosin, vitronectin, collagen, laminin, Glycosylation cell surface proteins, polyglycans, cadherin, heparin, tenascin, CD 54, CAM, elastin and FAK; wherein comprising inhibiting the secretion of fibronectin, wherein comprising administering to a subject, in need thereof, an appropriate amount of triterpenoidal saponins comprising two or more angeloyl groups, or a compound comprises a triterpene which comprises any two of angeloyl, tigloyl, senecioyl, perferable two angeloyl groups, and a sugar moiety, glucose, galactose, rhamnose, arabinose, xylose,
- This invention provides a composition comprising an effective amount of the compound of any one of compound selected from the above formula or a salt, ester, metabolite or derivative thereof as a medicament for reducing adhesion protein; wherein the adhesion proteins comprise fibronectin, integrins family, Myosin , vitronectin, collagen, laminin, Glycosylation cell surface proteins, polyglycans, cadherin, heparin, tenascin, CD 54, CAM, elastin and FAK, for inhibiting the growth, migration, metastasis of cancer, wherein the cancers comprise breast cancer, leukocyte cancer, liver cancer, ovarian cancer, bladder cancer, prostate cancer, skin cancer, bone cancer, brain cancer, leukemia cancer, lung cancer, colon cancer, CNS cancer, melanoma cancer, renal cancer or cervix cancer.
- the adhesion proteins comprise fibronectin, integrins family, Myosin , vitronectin, collagen, laminin, Glycosy
- This invention also provides a composition comprising the above described compounds or their derivatives for reducing adhesion protein, wherein the adhesion proteins comprise fibronectin, integrins family, Myosin , vitronectin, collagen, laminin,
- Glycosylation cell surface proteins comprising administering to a subject
- compositions comprising any one of triterpenoid saponins with the following formula: 3-O- ⁇ [/?-D-galactopyranosyl (1 ⁇ 2)]-[ ⁇ -L-arabinofuranosyl (1 ⁇ 3)]-/?-D- glucuronopyranoside butyl ester ⁇ -21-O-acetyl-22-O-angeloyl-3/?,16 ⁇ ,21/?,22 ⁇ ,28- pentahydroxyolean-12-ene.
- This invention provides a composition comprising the compounds as described above effective in regulating or reducing adhesion protein, wherein the adhesion proteins comprise fibronectin, integrins family, Myosin , vitronectin, collagen, laminin, Glycosylation cell surface proteins, polyglycans, cadherin, heparin, tenascin, CD 54, CAM, elastin and FAK; inhibiting venous insufficiency, particularly hemorrhoids or inhibiting of leg swelling, and inhibiting cancer growth.
- the cancer includes but is not limited to bladder cancer, bone, cancer, skin cancer and ovarian cancer.
- This invention also provides a composition for regulating or reducing adhesion protein, wherein the adhesion protein comprising fibronectin, integrins family, CD44, Myosin Vl, vitronectin collagen, laminin, Glycosylation cell surface proteins, polyglycans and FAK; inhibiting venous insufficiency, particularly hemorrhoids or inhibition of leg swelling, or inhibiting cancer growth comprising any of compounds selected from the following compounds:
- This invention provides a composition for regulating or reducing adhesion protein, wherein the adhesion proteins comprise fibronectin, integrins family, Myosin , vitronectin, collagen, laminin, Glycosylation cell surface proteins, polyglycans, cadherin, heparin, tenascin, CD 54, CAM, elastin and FAK; wherein blocking the migration, metastasis of cancer cells inhibiting venous insufficiency, particularly hemorrhoids or inhibiting leg swelling, inhibiting cancer growth comprising any of the compounds selected from the following: A1) 3-O-[ ⁇ -D-galactopyranosyl (1 ⁇ 2)]- ⁇ -L-arabinofuranosyl(1 ⁇ 3)- ⁇ -D- glucuronopyranosyl-21-0-angeloyl,22-0-benzoyl-3 ⁇ , 15 ⁇ , 16 ⁇ , 21 ⁇ , 22 ⁇ , 28- hexahydroxyolean-12-ene,
- Triterpenoid saponins with the characteristic structures mentioned above in this invention can be used to inhibit venous insufficiency, particularly hemorrhoids or inhibit leg swelling
- Triterpenoid saponins with the characteristic structures mentioned above in this invention can be used to block the migration, metastasis of cancer cells, reduce or inhibit cancer growth.
- the cancers are included but not limited to Leukemia cancer, Lung cancer, Colon cancer, CNS cancer, Melanoma cancer, Ovarian cancer, Renal cancer, Prostate cancer, Breast cancer, bladder cancer, cervix cancer, liver cancer, bone cancer, brain cancer and Skin cancer.
- Triterpenoid saponins with the characteristic structures mentioned above in this invention can be used to affect cell membrane structure and adhesion process..
- the method provides a method of regulating or reducing adhesion proteins to blocks the migration, metastasis of cancer cells, growth of cancers.
- the method comprises reducing the adhesion ability of the cancer cells.
- the adhesion proteins comprise IgSF CAM, Selectins, lntegrin or Cadherins.
- the adhesion proteins comprise fibronectin, integrins family, Myosin , vitronectin, collagen, laminin, Glycosylation cell surface proteins, polyglycans, cadherin, heparin, tenascin, CD 54, CAM, elastin and FAK;
- the compound is a triterpenoidal saponin or sapogenin, wherein the triterpenoidal saponin comprises at least any one or two of an angeloyl group, tigloyl group, or senecioyl group, or their combinations thereof at carbon 21 and/or 22, or 28, directly attached to the sapogenin or attached to a sugar moiety can be used to to treat varicose vein disease, inhibit venous insufficiency, particularly hemorrhoids or inhibit leg swelling, reduce or inhibit cancer growth.
- the compound is a five ring triterpene saponin comprising at least two angeloyl groups, tigloyl group, or senecioyl group, or their combinations thereof and a sugar moiety.
- the angeloyl groups are attached to a side chain at the end of the five rings and a sugar moiety is attached to a side chain of the ring at the other end of the five rings.
- the compound comprises at least two angeloyl groups, a tigloyl group, or a senecioyl group, or combinations thereof and a sugar moiety.
- the angeloyl groups and the sugar moiety are attached to the side chains of the backbone of the compound respectively.
- the angeloyl can be replaced by a functional group which functions as an angeloyl group.
- a sugar moiety or chain is at C3 or other positions, comprising one or more sugar selected from, but is not limited to glucose, galactose, rhamnose, arabinose, xylose, fucose, allose, altrose, gulose, idose, lyxose, mannose, psicose, ribose, sorbose, tagatose, talose, fructose, alduronic acid, glucuronic acid, galacturonic acid, or derivatives thereof, or the combination thereof preferably D- glucose, D-galactose, L-rhamnose, /.-arabinose, alduronic acids of D- glucuronic acid or D-galacturonic acid, or their combinations thereof, or their derivatives thereof.
- CH 3 or CH 2 OH or COOH or acetyl group may attach at C 23-30 independently.
- the activities of a saponin compound for regulating or inhibiting tumor cell growth are based on or attributed to its structure that has the functional group(s) such as angeloyl group, tigloyl group, senecioyl group or acetyl group, or their combinations thereof.
- This invention provides a composition comprising the compounds with the structure of:
- R1 and R2 comprise angeloyl groups, tigloyl groups, senecioyl groups or acetyl group or their combinations, preferable wherein the R1 and R2 comprise angeloyl groups.
- R1 and R2 comprise compounds selected from angeloyl, acetyl, tigloyl, senecioyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic, heteroraryl, or acid with 2 to 5 carbon or derivative thereof.
- R1 and R2 comprise angeloyl groups, tigloyl groups, senecioyl groups or acetyl group or their combinations, preferable wherein the R1 and R2 comprise angeloyl groups.
- R1 and R2 comprise compounds selected from angeloyl, acetyl, tigloyl, senecioyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic, heteroraryl, or acid with 2 to 5 carbon or derivative thereof.
- the compound further comprises a sugar moiety.
- the sugar moiety comprises glucose, galactose or arabinose or combination thereof.
- the sugar moiety comprises at least one sugar, or glucose, or galactose, or rhamnose, or arabinose, or xylose, or alduronic acid, or glucuronic acid, or galacturonic acid, or their derivative thereof, or the combination thereof.
- the R1 or R 2 may be attached in other position of the structure.
- R1 , R2 or R3 comprise angeloyl groups, tigloyl groups, senecioyl groups or acetyl group or their combinations, preferable wherein at least two of the R1 , R2 and R3 comprise angeloyl groups.
- at least two of R1, R2 and R3 comprise compounds selected from angeloyl, acetyl, tigloyl, senecioyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic, heteroraryl, or acid with 2 to 5 carbon or derivative thereof.
- At least one of R1 , R2 and R3 comprise a sugar moiety comprising two compounds selected from angeloyl, acetyl, tigloyl, senecioyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic, heteroraryl, or acid with 2 to 5 carbon or derivative thereof.
- the compound comprises a sugar moiety.
- the sugar moiety is attached at one end of structure (d), opposite to R1 , R2 and R3.
- the sugar moiety comprises glucose, galactose or arabinose or combination thereof.
- the sugar moiety comprises at least one sugar, or glucose, or galactose, or rhamnose, or arabinose, or xylose, or alduronic acid, or glucuronic acid, or galacturonic acid, or their derivative thereof, or the combination thereof.
- the sugar moiety comprises one or more sugar selected from, but is not limited to glucose, galactose, rhamnose, arabinose, xylose, fucose, allose, altrose, gulose, idose, lyxose, mannose, psicose, ribose, sorbose, tagatose, talose, fructose, alduronic acid, glucuronic acid, galacturonic acid, or derivatives thereof, or the combination thereof.
- the R1, R 2 and R3 may be attached in other position of the structure.
- the compound is triterpenoid saponin comprise comprises at least two angeloyl groups, tigloyl groups, senecioyl groups or acetyl group or their combinations, preferable wherein at least two angeloyl groups.
- At least one of the side bonds comprise a sugar moiety comprising two compounds selected from angeloyl, acetyl, tigloyl, senecioyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic, heteroraryl, or acid with 2 to 5 carbon or derivative thereof.
- the compound comprises a sugar moiety.
- the sugar moiety comprises glucose, galactose or arabinose or combination thereof.
- the sugar moiety comprises at least one sugar, or glucose, or galactose, or rhamnose, or arabinose, or xylose, or alduronic acid, or glucuronic acid, or galacturonic acid, or their derivative thereof, or the combination thereof.
- the sugar moiety comprises one or more sugar selected from, but is not limited to glucose, galactose, rhamnose, arabinose, xylose, fucose, allose, altrose, gulose, idose, lyxose, mannose, psicose, ribose, sorbose, tagatose, talose, fructose, alduronic acid, glucuronic acid, galacturonic acid, or derivatives thereof, or the combination thereof.
- sugar selected from, but is not limited to glucose, galactose, rhamnose, arabinose, xylose, fucose, allose, altrose, gulose, idose, lyxose, mannose, psicose, ribose, sorbose, tagatose, talose, fructose, alduronic acid, glucuronic acid, galacturonic acid, or derivatives thereof, or the combination thereof.
- a triterpene comprise the following structure has activities of reducing adhesion proteins to blocks the migration, metastasis of cancer cells, growth of cancers.
- R1 , R2 and R3 comprise compounds selected from angeloyl, acetyl, tigloyl, senecioyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, heterocylic, heteroraryl, or acid with 2 to 5 carbon or derivative thereof.
- At least one of R1 , R2 and R3 comprise a sugar moiety comprising two compounds selected from angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic, heteroraryl, or acid with 2 to 5 carbon or derivative thereof.
- R1 , R2 or R3 comprise angeloyl groups, tigloyl groups, senecioyl groups or acetyl group or their combinations, preferable wherein at least two of the R1 , R2 and R3 comprise angeloyl groups.
- R5 comprises sugar moiety.
- the sugar moiety comprises at least one sugar, or glucose, or galactose, or rhamnose, or arabinose, or xylose, or alduronic acid, or glucuronic acid, or galacturonic acid, or their derivative thereof, or the combination thereof.
- the sugar moiety comprises one or more sugar selected from, but is not limited to glucose, galactose, rhamnose, arabinose, xylose, fucose, allose, altrose, gulose, idose, lyxose, mannose, psicose, ribose, sorbose, tagatose, talose, fructose, alduronic acid, glucuronic acid, galacturonic acid, or derivatives thereof, or the combination thereof.
- the sugar moiety comprise glucose, galactose or arabinose, or combination thereof, or derivatives thereof.
- the sugar moietiy comprise alduronic acids, galactose and arabinose, wherein the alduronic comprise glucuronic acid or galacturonic acid.
- the sugar moiety comprise alduronic acids, glucose and arabinose, wherein the alduronic comprise glucuronic acid or galacturonic acid.
- the R1 , R 2 and R3 may be attached in other position of the structure.
- the compound is triterpenoid saponin comprise comprises at least two angeloyl groups, tigloyl groups, senecioyl groups or acetyl group or their combinations, preferable wherein at least two angeloyl groups.
- At least one of the side bonds comprise a sugar moiety comprising two compounds selected from angeloyl, acetyl, tigloyl, senecioyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic, heteroraryl, or acid with 2 to 5 carbon or derivative thereof.
- the compound comprises a sugar moiety.
- the sugar moiety comprises glucose, galactose or arabinose or combination thereof.
- the sugar moiety comprises at least one sugar, or glucose, or galactose, or rhamnose, or arabinose, or xylose, or alduronic acid, or glucuronic acid, or galacturonic acid, or their derivative thereof, or the combination thereof.
- the sugar moiety comprises one or more sugar selected from, but is not limited to glucose, galactose, rhamnose, arabinose, xylose, fucose, allose, altrose, gulose, idose, lyxose, mannose, psicose, ribose, sorbose, tagatose, talose, fructose, alduronic acid, glucuronic acid, galacturonic acid, or derivatives thereof, or the combination thereof.
- sugar selected from, but is not limited to glucose, galactose, rhamnose, arabinose, xylose, fucose, allose, altrose, gulose, idose, lyxose, mannose, psicose, ribose, sorbose, tagatose, talose, fructose, alduronic acid, glucuronic acid, galacturonic acid, or derivatives thereof, or the combination thereof.
- a composition comprising an effective amount of compound selected from the above formula or a salt, ester, metabolite or derivative thereof as a medicament for regulating or reducing adhesion protein, blocking the migration, metastasis of cancer cells, inhibiting tumor or cancer cell growth and for treating cancer, wherein the cancers comprise breast, leukocyte, liver, ovarian, bladder, prostate, skin, bone, brain, leukemia, lung, colon, CNS, melanoma, renal and cervix cancer.
- a compound or sapongenin comprises the structure (d) or (e) has anti-cancer or inhibiting virus activities.
- a composition for regulating or reducing adhesion protein, blocking the migration, metastasis of cancer cells, treating cancers or inhibiting virus comprising a compound, wherein the compound is a triterpene, which comprises at least two side chains which comprise angeloyl groups, wherein the side chains are at adjacent carbon in trans position.
- the side chains are at alternate carbon in cis position.
- the side chains are at alternate carbon in trans position.
- the side chains are attached an acyl.
- the side chains are attached an unsaturated group.
- the side chains are in non-adjacent carbon cis or trans position.
- the side chains comprise a functional group capable of performing the function of angeloyl group.
- the above compounds can be used for regulating or reducing adhesion protein, blocking the migration, metastasis of cancer cells, inhibiting tumor cell growth, reducing leg swelling, symptoms of chronic venous insufficiency, peripheral edema, antilipemic, chronic venous disease, varicose vein disease, varicose syndrome, venous stasis, expectorant, peripheral vascular disorders, by administering to a subject in need thereof, an effective amount of the above described compounds.
- This invention provides a method for inhibiting tumor cell growth, regulating cell growth, reducing inflammation, in a subject, comprising administering to a subject, in need thereof, an effective amount of the compound which comprises any of the above structures to said subject.
- the cancers are included but not limited to Leukemia cancer, Lung cancer, Colon cancer, CNS cancer, Melanoma cancer, Ovarian cancer, Renal cancer, Prostate cancer, Breast cancer, bladder cancer, cervix cancer, liver cancer, bone cancer, brain cancer and Skin cancer.
- This invention also provides a method for reducing swelling, reducing symptoms of chronic venous insufficiency, peripheral edema, antilipemic, chronic venous disease, varicose vein disease, varicose syndrome, venous stasis, Expectorant, peripheral vascular disorders, cerebro-organic convulsion, cerebral circulation disorder, cerebral edema, psychoses, dysmenorrhea!, hemorrhoids, episiotomies, peripheral edema formation or postoperative swelling; for reducing symptoms of leg pain; for treating pruritis, lower leg volume, for reducing symptoms of pain; thrombosis, thromophlebitis; for preventing gastric ulcers antispasmotic, comprising administering to a subject, in need thereof, an effective amount of the composition of this invention.
- This invention provides a composition comprising the compounds provided in the invention for treating cancers; for inhibiting virus; for preventing cerebral aging; for improving memory; improving cerebral functions, for curing enuresis, frequent micturition, urinary incontinence.dementia, Alzheimer's disease, autism, brain trauma, Parkinson's disease or other diseases caused by cerebral dysfunctions; for treating arthritis, rheumatism, poor circulation, arteriosclerosis, Raynaud's syndrome, angina pectoris, cardiac disorder, coronary heart disease, headache, dizziness, kidney disorder; cerebrovascular diseasea; inhibiting NF-Kappa B activation; for treating brain edema, sever acute respiratory syndrome, respiratory viral diseases, chronic venous insufficiency, hypertension, chronic venous disease, anti-oedematous, anti inflammatory, hemonhoids, peripheral edema formation, varicose vein disease, flu, post traumatic edema and postoperative swelling;for inhibiting blood clot, for inhibiting ethanol absorption; for
- This invention provides a composition for AntiMS, antianeurysm, antiasthmatic, antibradykinic, anticapillarihemorrhagic, anticephalagic, anticervicobrachialgic, antieclamptic, antiedemic, antiencaphalitic, antiepiglottitic, antiexudative, antiflu, antifracture, antigingivitic, antihematomic, antiherpetic, antihistaminic, antihydrathritic, antimeningitic, antioxidant, antiperiodontic, antiphlebitic, antipleuritic, antiraucedo, antirhinitic, antitonsilitic, antiulcer, antivaricose, antivertiginous, cancerostatic, corticosterogenic, diuretic, fungicide, hemolytic, hyaluronidase inhibitor, lymphagogue, natriuretic, pesticide, pituitary stimulant, thymolytic, vasoprotective, and venotonic treatment.
- Alkenyl means unsaturated linear or branched structures and combinations thereof, having 1-7 carbon atoms, one or more double bonds therein.
- alkenyl groups include vinyl, propenyl, isopropenyl, butenyl, s- and t-butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, and hexadienyl.
- An aryl is a functional group of organic molecule derived from an aromatic compound such as benzene, a 6-14 membered carbocyclic aromatic ring system cpmprising 1-3 benzene rings.
- rings are fused together, so that adjacent rings share a common bond.
- aromatic rings include phenyl and naphthyl.
- the aryl group may be substituted with one or more sunstitutes independnetly selected from halogen, alkyl or alkoxy.
- Acyl is a functional group obtained from an organic acid by the removal of the carboxyl.
- Acyl groups can be written as having the general formula -COR, where there is a double bond between the carbon and oxygen.
- the names of acyl groups typically end in -yl, such as formyl, acetyl, propionyl, butyryl and benzoyl.
- Benzoyl is one of acyls, C ⁇ HsCOR, obtained from benzoic acid by the removal of the carboxyl.
- Heterocyclic compound - a compound containing a heterocyclic ring which refers to a non-aromatic ring having 1-4 heteroatoms said ring being isolated or fused to a second ring selected from 3- to 7-membered alicyclic ring containing 0-4 heteroatoms, aryl and heteroaryl , wherein said heterocyclic comprises pyrrolidinyl , pipyrazinyl , morpholinyl, trahydrofuranyl, imidazolinyl, thiomorpholinyl, and the like.
- Alkanoyl is the general name for an organic functional group RCO-, where R represents hydrogen or an alkyl group.
- alkanoyl is selected from acetyl, propionoyl, butyryl, isobutyryl, pentanoyl and hexanoyl.
- Alkenoyl is alkenylcarbonyl in which alkenyl is defined above. Examples are pentenoyl(tigloyl) and hexenoyl(angeloyl).
- Alkyl is a radical containing only carbon and hydrogen atoms arranged in a chain, branched, cyclic or bicyclic structure or their combinations, having 1-18 carbon atoms. Examples include but are not limited to methyl, ethyl, propyl isopropyl, butyl, s- and t- butyl, pentyl, hexyl, heptyl, octyl, nonyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
- Benzoyl alkyl substituted alkanoyl is refer to straight or branched C1-C6 alkanoyl substituted with at least one benzoyl and at least one alkyl, wherein the benzoyl is attached to a straight or branched C1-C6 alkyl.
- a benzoyl alkyl substituted alkanoyl is benzoyl methyl isobutanoyl.
- a sugar moiety is a segment of molecule comprising one or more sugars or derivatives thereof or alduronic acid thereof, lsobutyryl is Synonym of 2-Methylpropanoyl Y and Y3 represent the same compound.
- YM and (ACH-Y) represent the same compound.
- This invention provides a method of altering the characteristic of cancer cell membrane to block the migration, metastasis of cancer cells or inhibit the growth of cancers or anti- angiogenesis.
- This invention provides a method of inhibiting the growth, migration, metastasis of cancer by altering the characteristic of membrane of cancer cell, wherein the characteristic comprise adhesion protein; wherein the cancers comprise breast cancer, leukocyte cancer, liver cancer, ovarian cancer, bladder cancer, prostate cancer, skin cancer, bone cancer, brain cancer, leukemia cancer, lung cancer, colon cancer, CNS cancer, melanoma cancer, renal cancer or cervix cancer, wherein the method is administering contacting Xanifolia YO, Y1 , Y2, Y, Y7, Y8, Y9, Y10, or a salt, ester, metabolite thereof.
- This invention provides a composition and method for inhibiting the growth, migration, metastasis of cancer by altering the adhesion characteristic of membrane of cancer cell, wherein the cancers comprise breast cancer, leukocyte cancer, liver cancer, ovarian cancer, bladder cancer, prostate cancer, skin cancer, bone cancer, brain cancer, leukemia cancer, lung cancer, colon cancer, CNS cancer, melanoma cancer, renal cancer or cervix cancer, wherein the method is administering contacting Xanifolia YO, Y1 , Y2, Y, Y7, Y8, Y9, Y10, or a salt, ester, metabolite thereof. In an embodiment the method is administering contacting the compound selected from formula in this application.
- Xanifolia-Y is an alternate or supplemental agent to DNA- inhibition or microtubule-targeting drugs. It could be beneficial if it is used singly or in combination with other drugs of different mechanisms (block M-phase progression or DNA synthesis).
- Our inventions show combined effect of Xanifolia-Y and paclitaxel on inhibition of ES2 cells' growth (Detail in Experiment 14 U.S. Serial Nos.11/683198, filed on March 7, 2007)
- Xanifolia-Y extended the life span of tumor bearing mice. (See Experiments 7, 8, 9 in U.S. Serial Nos.11/683198, filed on March 7, 2007,). The animals died sooner if the treatment of Xanifolia-Y was delayed (comparing results of treatments started from 1, 4 or 10 days after tumor inoculation). The results show that Xanifolia-Y inhibits migration or metastasis of the inoculated cancer cells.
- Ovarian carcinoma cells express high levels of adhesion molecules. Adhesion proteins are present in both cancer cells and mesothelial cells. While the lost of adhesion blocks of the protein accessibility due to a result of modulating by Xanifolia-Y, In an embodiment, the interaction of Xanifolia-Y with membrane alter the adhesion protein's binding site(s).
- Xanifolia-Y are cytotoxic to tumor cells, In an embodiment it kills ovarian cancer cells.
- Our inventions show that Xanifolia-Y inhibits cancer cell growth and prolongs life-span of tumor bearing mice. Our studies also indicate that the sooner the drug-treatment, the longer the life-span of the tumor bearing animals is extended.
- Xanifolia-Y also has an effect in blocking or inhibiting migration or metastasis. The delay of Xanifolia-Y-treatment allows more chances for cancer cells to metastasize to the mesothelium lining in the peritoneal cavity which resulted in more tumor growth and shorter life span. Adhesive molecules play an important role in cell migration and metastasis.
- Xanifolia-Y inhibits cell attachment to culture flasks.
- Our experiment showed that Xanifolia-Y family inhibits the secrection of adhesion protein.
- Xanifolia-Y interferes with the function of the adhesive molecules.
- Xanifolia-Y blocks the function of the adhesive molecules.
- Xanifolia-Y modulates adhesive proteins. It is masking the adhesive proteins.
- Xanifolia-Y indirectly alters membrane structure that cause changes in protein conformation, or locations and result in loss of adhesion process.
- the adhesion proteins comprise fibronectin, integrins family, Myosin, vitronectin, collagen, laminin, Glycosylation cell surface proteins, polyglycans, cadherin, heparin, tenascin, CD 54, CAM, elastin and FAK, particular fibronectin.
- Fibronectin is a kind of glycoprotein that binds to membrane spanning receptor proteins comprising the integrins, collagen, fibrin and heparin sulfate. Fibronectin has been implicated in tumor development and metastasis.
- This application provides methods and compositions for modulating the gene expression of fibronectin, inhibiting the secretion of fibronectin, reducing the receptors of fibronectin, reducing the adhesion ability fibronectin, inhibiting the metastasis, or inhibiting cancer growth, wherein the method and composition comprises administering to the said subject as effective amount of compounds selected in this appliaction.
- Vitronectin is an abundant glycoprotein found in blood plasma and the extracellular matix. Vitronectin is involved in hemostasis and tumot malignancy.
- This application provides methods and compositions for modulating the gene expression of vitonectin, reducing the receptors of vitronectin, reducing the adhesion ability Vitronectin, inhibiting the metastasis, and inhibiting cancer growth, wherein the method and composition comprises administering of compounds selected in this appliaction.
- lntegrins are cell surface receptors that interact with the extracellular matix. They define cellular shape, mobility, and regulate the cell cycle, lntegrin plays a role in the attachment of cells to other cells, and also plays a role in the attachment of a cell to the material part of a tissue. Besides the attachment role, integrin also plays a role in signal transduction.
- This application provides method and composition for modulating the gene expression of integrins, wherein comprising inhibiting integrins, inhibititng the adhesion ability of integrins, inhibiting cancer cell metastasis and inhibiting cancer growth, wherein the method and composition comprise administering of compounds selected in this appliaction.
- Laminins are a family of glycoproteins that are an integral part of the structural scaffolding of basement membranes in almost every animal tissue. They are secreted and incorporated into cell-associated extrcellular matrices. Inhibiting the gene expression of laminins will reduce the adhesion ability of cells in order to inhibit the cell migration and metastasis of cancer cells.
- This application provides method and composition for modulating the gene expression of laminins, wherein comprising inhibiting laminins, inhibititng the adhesion ability of laminins inhibiting cancer cell metastasis and inhibiting cancer growth, wherein the method and composition comprise administering of compounds selected in this appliaction.
- CAM cell adhesion molecules
- CAM cell adhesion molecules
- This application provides method and composition for modulating the gene expression of CAM, wherein comprising inhibiting CAM, inhibititng the adhesion ability of CAM, inhibiting cancer cell metastasis and inhibiting cancer growth, wherein the method and composition comprise administering of compounds selected in this appliaction.
- Collagen is the main protein of conective tissue in mammal. Inhibiting the gene expression of collagen will reduce the adhesion ability of cells in order to inhibit the cell migration and metastasis of cancer cells.
- This application provides methods and compositions for modulating the gene expression of laminins, wherein comprising inhibiting laminins, inhibititng the adhesion ability of laminins inhibiting cancer cell metastasis and inhibiting cancer growth, wherein the method and composition comprise administering of compounds selected in this appliaction.
- Tenascin-C is an extracellular matrix protein on the cell. It is a positive factor for cancer growth, invasion and angiogenesis activities.
- This application provides methods and compositions for inhibiting Tenascin-C and inhibiting cancer growth, wherein the methods and compositions comprise administering of compounds selected in this appliaction.
- Angiogenesis is a process involving the growth of new blood vessels. It is a normal process in growth and development. However, this is also a fundamental step in the transition of tumors from a dormant state to a malignant state.
- the angiopoietins are protein growth factors that modulate angiogenesis.
- the identified angiopoietins comprise angiopoietin 1 , angiopoietin 2, angiopoietin 3, angiopoietin 4, angiopoietin 5, angiopoietin 6, angiopoietin 7, angiopoietin-like 1, angiopoietin-like 2, angiopoietin-like 3, angiopoietin-like 4, angiopoietin-like 5, angiopoietin-like 6, and angiopoietin-like 7.
- the angiopoietin 1 is a positive foctor to promote the new blood vessels.
- the angiopoietin 2 is antagonist of angiopoietin 1 , which is a negative factor for the growth of new blood vessels.
- This application provides methods and compositions for modulating angiopoietin and inhibiting cancer growth; wherein the cancers comprise breast, leukocyte, liver, ovarian, bladder, prostate, skin, bone, brain, leukemia, lung, colon, CNS, melanoma, renal and cervix cancer, wherein the methods and compositions comprise administering to the said subject as effective amount of compounds selected in this appliaction.
- the compounds in this application are positive regulating angiopoietin 2.
- the compounds in this application are negative regulating the angiopoietin 1.
- the results of the micro array experiment showed that compound Y and YM (ACH-Y) modulate the gene expression of angiopoietin family in ES2 cells. They promote angiopoietin 2 and inhibit angiopoietin 1 and angiopoietin-like 1 and angiopoietin-like 4.
- the compounds in this application are anti-angiogenesis, inhibiting cancer cell metastasis and inhibiting cancer growth, wherein the compounds comprise Xanifolia YO, Y1, Y2, Y, Y7, Y8, Y9, Y10, ACH-Y or a salt, ester, metabolite thereof and compounds selected from formula (1A), (1B), (1C) and (1 D).
- the method is administering contacting the compound in this application comprising Xanifolia YO, Y1 , Y2, Y, Y7, Y8, Y9, Y10, Xanifolia (x), Escin or Aescin or a salt, ester, metabolite thereof.
- the compound may be selected from formulas (1A), (1 B), (1C) and (1D).
- the compound comprises a triterpene backbone, two angeloyl groups and sugar moiety.
- the compound(s) are selected from Compound A to X and A1 to X1 in the application.
- the compound(s) are selected from Compound Z1 to Z7 in the application.
- Xanifolia Y modulates gene expression of the following genes (represented by gene symbol): Gene Symbol: ABL2, ADAMTS1 , AKR1C3, AMIGO2, ANGPT2, ANKRD11 , AP2B1 , APEH, APLP2, ARL10C, ARMC4, ARMCX1, ARMCX6, ARNTL2, ARNTL2, ATF3, ATP6V0E, ATP6V1 B2, ATP6V1C1, ATP6V1C1, BCL2A1 , BCL6, BRI3, BTD, C14orf109, C14orf78, C17orf32, C6orf65,C9orf10, C9orf103, CAD, CAV1, CAV2, CBLL1, CCL20, CD33L3, CEBPB, CEP4, CFH /// CFHL1 , CHRDL1 , CITED2, CITED2, CLDN14, CLN8, CLTA, CNAP1,
- Xanifolia Y and ACH-Y inhibited genes expression of the following genes: FN1 , ITGAV, LAMA4, LAMB2, LAMC1, LAMB1, LAMB1, LAMA4, LAMA5, LAMC1, LAMA2, LAMB1, LAMA3, SCAMP1, TICAM2, SCAMP1 , TICAM2, SCAMP1 , SCAMP1, CAMK2B, DL1 , ICAMS.CEECAMI, ICAM5.SCAMP1 , CAMK1G, CAMSAP1, MCAM, CAMTA1, CKN1, ALCAM 1 DCAMKL2, CEACAM3, CAMK2D, CAMK2B, SCAMP5, CAMK4, NCAM1, CAMK2G, MYH9, MYH10, MYO1D, MYO5A, MYLK, MYO6, MYO5A, MYO1C, MYLK, MYO6, MYLC2PL, MYO10, MYO6, TPM3, MYO1C,
- the method comprises reducing the adhesion ability of the cancer cells.
- the adhesion protein comprise fibronectin, integrins family, Myosin , vitronectin, collagen, laminin, Glycosylation cell surface proteins, polyglycans, cadherin, heparin, tenascin, CD 54, CAM, elastin and FAK, particular for fibronectin.
- Y/D is the ratio (in folds) of gene expression in cells treated with compound Y as compared with those of the no drug control (D),
- YIWD is the ratio of gene expression in cells treated with compound YM (ACH-Y, Y without sugar moiety) compared with those of the no drug control (D)
- the results of the microarray experiment showed that compound Y and YM(ACH-Y) inhibit fibronectin expression;
- the expression ratio of compound Y/Y3 to the control are -2.7, -2.6, -2.6, -2.5 folds detected by gene probes 212464_s_at; 216442_x_at; 211719x_at and 210495_x_at, respectively.
- Y/Y3 inhibits fibronectin expression; wherein the YM/ACH-Y also show minor fibronectin inhibition with the inhibiting ratio of -1.1 , -1.1 , -1.2, -1.1 folds by gene probes 212464_s_at; 216442_x_at; 211719_x_at and 210495_x_at, respectively .
- the results indicate that while YM is active but is less potent than Y/Y3.
- the results of the micro array experiment showed that compound Y and YM(ACH-Y) inhibit laminin expression;
- the expression ratio of compound Y/Y3 to the control are - 2.2, -2.0, -1.9, -1.6, -1.6 folds as detected by different probes; wherein the inhibiting ratio of YM/ACH-Y to the control are -2.0, -2.0, 1.1 , -1.7, -2.0 folds.
- the micro array experiment showed that compound Y and YM(ACH-Y) inhibit gene expression related to the adhesion molecule; wherein the inhibiting ratio of compound Y/Y3 to the control are -1.3 to -1.9 folds as detected by different probes; wherein the inhibiting ration of YM/ACH-Y to the control are -1.1 to -1.7 folds.
- the results of the micro array experiment showed that compound Y and YM(ACH-Y) inhibit collagen expression.
- the expression ratio of compound Y/Y3 to the control range from -1.3 to -3.0 folds; wherein the expression ratio of YM/ACH-Y to the control range from -1.1 to -3.6 folds
- integrin-associated signal transducer integrin, alpha 3 (antigen CD49C, alpha 3
- the results of the micro array experiment showed that compound Y and YM(ACH-Y) inhibit gene expression related to the integrin family in ES2 cells.
- the expression ratio of compound Y/Y3 to the control are ranging from -1.5 to -1.9 folds; wherein the expression ratio of YM/ACH-Y to the control are ranging from -1.1 to -2.5 folds.
- the results of the micro array experiment showed that compound Y and YM(ACH-Y) inhibit gene expression related to the myosin family in ES2 cells.
- the expression ratio of compound Y/Y3 to the control are ranging from -1.5 to -2.2 folds; wherein the expression ratio of YM/ACH-Y to the control are ranging from -1.2 to -2.1 folds.
- the results of the micro array experiment showed that compound Y and YM(ACH-Y) modulate the gene expression of angiopoietin family in ES2 cells.
- Fibronectin secretion is physiological and the determination of its quantity is based on the following criteria:
- Fibronectin is secreted from viable cells. Only cell with over 85% viable cells after drug-treatment are employed in these experiments. The viable cells were determined by MTT assay.
- the immuno-band intensity from each samples are normalized with cell mass.
- the cell mass was determined by the MTT assay and is assigned as a MTT unit for each cell sample.
- F11 For lung carcinoma cells (H460), at concentration of 20ug/ml, there are inhibitions of Fibronectin secretion ranged from 20-60%.
- F12A For bladder carcinoma cells (HTB-9), Xanifolia-Y (10 ug/ml) inhibits 50% of Fibronectin secretion.
- Angiopoietin 2 (Ang2) Up regulation of Angiopoietin 2 (Ang2) in ES2 cells with Xanifolia-Y treatment.
- ES2 human ovarian carcinoma cells
- Drug-treatment Cells cultures were treated with 5, 10 and 15 ug/ml (final concentration) of Xanifolia-Y3 [Y3-5, Y3-10, Y3-15]. or DMSO control [D-10]. After 24 hours, cells were suspended in 1 ml of SDS sample buffer (cell-extract). Samples (80 ul/lane) were applied to 10% SDS gel and electrophoresis was conducted with 100 volts for 2 hours. Protein was transferred to a nitrocellulose membrane electrophoretically.
- This invention provides compositions and methods for modulating the gene expression in cancer cells, wherein the modulating comprises of positive and negative regulation, wherein genes being modulatated are adhesion proteins; wherein modulation includes expression, production and secretion of adhesion proteins, wherein the adhesion proteins comprise fibronectin, integrins family, Myosin , vitronectin, collagen, laminin, cadherin, heparin, tenascin, CD 54, CAM.
- This invention provides compositions and methods for modulating angiopoietins, wherein comprises positive regulating the angiopoietin 2, wherein comprises negative regulating angiopoietin 1.
- composition and method of this invention comprises a triterpene wherein acylation group at carbon position 21 and/or 22 of the triterpene is necessary for the function and are selected from angeloyl, acetyl, alkanoyl, alkenoyl and acyl group.
- the sugar moiety (ies) at position 5 of the triterpene is important for enchancing activity of these compounds.
- microarray experiments were done in studying the gene expression. Total number of 54676 genes has been studied.
- ES2 cells were seeded in a T-25 flask with 4.5 million cells per flask for 24 hours. Cell culture was replaced with fresh medium with xanifolia- Y (Y) or DMSO no drug control (D) for 24 hours. Cells were then harvested for RNA isolation. Three experiments were done. RNA extraction, labeling, hybridization, and data analysis. RNA was extracted from tumor cells using the Qiagen RNeasy Kit. RNA quality and quantity was checked by the Agilent BioAnalyzer and the NanoDrop ® ND-1000 spectrophotometer respectively before further manipulation.
- the first and second cDNA strands were synthesized from 20 ng of total RNA using the Affymetrix T7 oligo(dT) primer protocol and kit for the two- cycle amplificaton.
- the cDNA was reverse transcribed by in vitro transcription using the MegaScript kit from Ambion. 15.0 ⁇ g of the labeled cRNA was fragmented and re-checked for concentration using the NanoDrop ® ND-1000 spectrophotometer.
- a hybridization cocktail containing Affymetrix spike-in controls and fragmented labeled cRNA was loaded onto the Human U 133 Plus 2.0 GeneChip ® oligonucleotide array.
- the Affymetrix array (Affymetrix, Inc.Santa Clara, CA) is comprised of over 1 ,300,000 unique oligonucleotide features that represent greater than 38,500 well-substantiated human genes.
- the array was hybridized for 16 hours at 45°C with rotation at 60 rpm then washed and stained with a strepavidin, R- phycoerythrin conjugate stain on the Affymetrix Fluidicis Station 450. Signal amplification was done using biotinylated antistreptavidin.
- the arrays were scanned using the GeneChip ® 3000 confocal laser scanner with autoloader. The images were analyzed and quality control metrics recorded using Affymetrix GCOS software version 1.4. Lastly, the expression value for each gene was calculated using dChip PM-only model based or Plier algorithm. Data Analysis Methods
- the raw data in the .CEL files were normalized by the GCRMA method (robust multi- array analysis). It is implemented in Bioconductor (http://www.bioconductor.org/). The raw signal intensity data were normalized, background corrected and summarized based on certain statistical models, and an expression value, in Ioq2-scale, is obtained per chip per probe set. Then the null hypothesis was tested that there's no significant changes in gene expression between the treatment pairs. This was done by LIMMA and is also implemented in Bioconductor. It uses empirical Bayes method to estimate the variance in gene expression. One comparison was made, namely, High Grade vs. Low Grade. The raw p-values were adjusted by the Benjamnin-Hochberg method for false discovery rate (FDR) control.
- FDR false discovery rate
- ES2 cells were grew in T-25 flask with RPMI 1640 medium over night before drug-treatment.
- Drug-treatment cells cultures were replaced with fresh RPMI medium with Xanifolia-Y (10 ug/ml final concentration) or DMSO (as control) at 0 hour.At 1 , 2, 4, 8 and 24 hour, aliquot of culture medium was taken out for Fibronectin determination. Fibronectin was determined by Western blot with monoclonal antibody (SIGMA) specific to human Fibronectin only. Results (also see Figure 1): 1. Cells treated with DMSO (as no drug control) secret Fibronectin to medium and the amount of Fibronectin accumulated with time. There is no or only minimally secretion of Fibronectin observed in cell culture treated with Xanifolia-Y.
- Fibronectin immunoband was not observed in RPMI medium with fetal bovine serum, or employing the normal mouse serum (NS1).
- ES2 cells were grew in RPMI 1640 medium over night before drug-treatment.
- Drug-treatment cells cultures were replaced with fresh RPMI medium containing
- Xanifolia-Y (10 ug/ml final concentration) or DMSO (as control) at 0 hour.
- culture medium was replaced with fresh culture medium without drug.
- aliquot of culture medium was taken out for Fibronectin determination.
- Fibronectin (FN) was determined by Western blot with monoclonal antibody (SIGMA) specific only to human Fibronectin. Results (also see Figure 2):
- ES2 cells were grew in RPMI 1640 medium over night before drug-treatment.
- Drug-treatment cells cultures were replaced with fresh RPMI medium containing Xanifolia-Y (10 ug/ml final concentration) or DMSO (as control) at 0 hour. At 2, and 18 hour, aliquot of culture medium was taken out for Fibronectin determination (Western blot method). Cell viability at 18 hours was determined by MTT assay. Cultures were replaced with RPMI medium with MTT and incubated for an hour. The formation of formazan was dissolved in DMSO and OD at 570nm was measured. Results (also see Figure 2): • Over 95% of cells after 18 hours of Y-treatment were viable as determined by MTT assay.
- ES2 cells were grew in RPMI 1640 medium over night before drug-treatment.
- Drug-treatment cells cultures were replaced with fresh RPMI medium containing DMSO (as control) [D]; Xanifolia-Y (10 ug/ml) [Y]; or Paclitaxel 10 or 50 ng/ml [T10, ro T50].
- the amount of Fibronectin secreted by cells into medium was determined by Western blot assay.
- the amount of Fibronectin secreted per cells basis was determined by dividing the Western-band intensity with the MTT unit.
- ES2 cells treated with 10 ng/ml or 50 ng/ml Taxel secret 105% or 97%, respectively, of Fibronectin into medium during 24 hours of treatment.
- Y-treated ES2 cells secreted 62% of control (a reduction of 38%).
- Cells Hey ⁇ A (human ovarian carcinoma cells) were grew in RPMI 1640 medium to 90% confluent before drug-treatment.
- Drug-treatment Cells cultures were replaced with fresh RPMI medium containing either DMSO (as control) [D1]; or Xanifolia-Y (10, 15, or 20 ug/ml) [Y1, Y2 and Y3]. Aliquot of medium was removed as 0 hours sample and no FN was detected at this time. After 24 hours, aliquot of culture medium was taken out for Fibronectin determination (Western blot method). Cell viability at 24 hours was determined by MTT assay. Cultures were replaced with RPMI medium (5 ml) with MTT and incubated for an hour.
- Lung cells (H460) are sensitive to Y in inhibition of FN secretion. Based on MTT results, cells are still viable at 20 ug/ml Y, but the inhibition of FN is over 60%.
- the MTT assay showed that the growth of cells treated with 10 ug/ml Y reduced to 77% - 91% compared to the DMSO control. • The Western blot shows that the FN band intensity of Y-treated samples are reduced. After corrected with the MTT unit (equivalent to cell mass) there is about 50% reduction of FN band intensity per cell mass.
- the MTT assay showed that the growth of cells with Y, Es10 and Es20 are 89%, 90% and 82%, respectively as compared to the DMSO control.
- AKOH-Y the Y3 without diangeloyl group
- all samples have some degrees of inhibition of FN secretion from ES2 cells.
- 80 ug/ml of AKOH-Y which is 4 times higher concentration used in others saponins (10 ug/ml) still have no effect on inhibition of FN secretion on ES2 cells.
- ES2 human ovarian carcinoma cells
- RPMI 1640 medium 1.5 million cells were seeded in a T25 flask and grown for 24 hours before drug-treatment.
- the blot was then incubated with the first antibodies (mouse anti-FN, specific to human FN, SIGMA F0916 and mouse anti-beta actin, SIGMA A5316) and second antibody (Anti-mouse IgG AP conjugated, Promega S3721).
- the immuno-bands were developed with BCIP/NBT color development system (Promega S3771). Determination of Western band intensity: The band-images of Western blot were captured with a digital camera (3-5 pictures were taken per gel) and the intensity of bands was determined using "Image J" software. FN concentrations were normalized with the cellular beta-Actin concentrations. Fibronectin secreted into medium and inside Y-treated cells were determined and compare to controls (DMSO-treated cells).
- mice 2-3 months old were transplanted sc with ES2 (human ovarian cancer) cells. • Five days after the transplant (day one), mice were divided into two groups (H and J) with two animals in each group.
- mice On days 1-5, and 8-10 mice received daily drug administration of Xanifolia- Y, by i.p. route at dose of 2.5 mg/kg. • Group J mice received no drug-treatment.
- Group H Mice received drug-treatment, tumor size is 10 mm in 10 days
- Group J Mice received no drug-treatment, tumor size is 18 mm in 10 days The tumor size is 45% smaller in mice with drug than the mice with no drug in 10 days period.
- Athymic Nu/Nu mice (5-6 weeks old) are divided into three groups (O, P and Q) with 5-6 animals in each group.
- mice On day 0, all mice were transplanted intra-peritoneally with ES2 (human ovarian cancer) cells.
- the median survival time of tumor bearing mice without drug-treatment is 24 days.
- the median survival time of tumor bearing mice with drug-treatment starting on day 4 after tumor inoculation is 58 days (extension of life span of 141%); and
- the median survival time of tumor bearing mice with drug-treatment started on day 10 after tumor inoculation is 31 days (extension of life span of 29%).
- ES2 or Hey ⁇ A cells were plated in T25 flasks with medium containing 5 ug/ml of Xanifolia-Y. Cultures were incubated for 5 hours. Attached cells were removed from flasks by trypsinization and the amounts were counted. Compare to no drug controls, 86 ⁇ 4 % of ES2 cells and 67 ⁇ 8 % of Hey ⁇ A cells were found attached to flasks under this condition. At 5 ug/ml Xanifolia-Y, over 90% of unattached cells are alive as determined by the trypan Blue exclusion assay and by their ability to re-attach to flasks when plating in medium without Xanifolia-Y. However, with 10 ug/ml Xanifolia-Y, less than 40% of cells attached to flasks and many of them are dead cells. This experiment shows that Xanifolia-Y inhibits cells adhesion process.
- Meothods ES2 (human ovarian carcinoma cells) were grew in RPMI 1640 medium. 4.5 million cells were seeded in a T75 flask and grown for 24 hours before drug-treatment.
- Drug-treatment Cells cultures were treated with 5, 10 and 15 ug/ml (final concentration) of Xanifolia-Y3 [Y3-5, Y3-10, Y3-15]. or DMSO control [D-10]. After 24 hours, cells were suspended in 1 ml of SDS sample buffer (cell-extract). Samples (80 ul/lane) were applied to a 10% SDS gel and electrophoresis was conducted with 100 volts for 2 hours. Protein was transferred to a nitrocellulose membrane electrophoretically.
- the nitrocellulose blot was blocked with 5% non-fat dry milk in PBS. The blot was then incubated with the first antibodies (goat anti-Ang2, SIGMA A0851) and second antibody (donkey anti-goat AP conjugated, Promega V115A). The immuno-bands were developed with BCIP/NBT color development system (Promega S3771).
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AU2008244648A AU2008244648A1 (en) | 2007-02-16 | 2008-02-15 | Blocking the migration or metastasis of cancer cells by affecting adhesion proteins and the uses of new compounds thereof |
JP2009550096A JP2010519219A (en) | 2007-02-16 | 2008-02-15 | Blocking cancer cell migration or metastasis by affecting adhesion proteins and use of the novel compounds |
EP08725693A EP2121715A4 (en) | 2007-02-16 | 2008-02-15 | Blocking the migration or metastasis of cancer cells by affecting adhesion proteins and the uses of new compounds thereof |
CA002676791A CA2676791A1 (en) | 2007-02-16 | 2008-02-15 | Blocking the migration or metastasis of cancer cells by affecting adhesion proteins and the uses of new compounds thereof |
CN200880012065A CN101772511A (en) | 2007-02-16 | 2008-02-15 | Blocking the migration or metastasis of cancer cells by affecting adhesion proteins and the uses of new compounds thereof |
CN200980112951.5A CN101998964B (en) | 2008-02-15 | 2009-02-13 | Blocking the metastasis of cancer cells and the uses of new compounds thereof |
PCT/US2009/034115 WO2009117196A1 (en) | 2008-02-15 | 2009-02-13 | Blocking the metastasis of cancer cells and the uses of new compounds thereof |
CA2715501A CA2715501A1 (en) | 2008-02-15 | 2009-02-13 | Blocking the metastasis of cancer cells and the uses of new compounds thereof |
EP09721583A EP2254899A4 (en) | 2008-02-15 | 2009-02-13 | Blocking the metastasis of cancer cells and the uses of new compounds thereof |
AU2009226063A AU2009226063A1 (en) | 2008-02-15 | 2009-02-13 | Blocking the metastasis of cancer cells and the uses of new compounds thereof |
US12/541,713 US8735558B2 (en) | 2005-02-14 | 2009-08-14 | Blocking the migration or metastasis of cancer cells by affecting adhesion proteins and the uses of new compounds thereof |
US12/856,322 US8586719B2 (en) | 2005-04-27 | 2010-08-13 | Triterpenes for modulating gene expression and cell membrane, and as antiprotozoal agents |
US13/841,053 US9382285B2 (en) | 2004-09-07 | 2013-03-15 | Methods and compounds for modulating the secretion or expression of adhesion proteins or angiopoietins of cells |
US15/181,631 US10213451B2 (en) | 2004-09-07 | 2016-06-14 | Methods and compounds for modulating the secretion or expression of adhesion proteins or angiopoietins of cells |
US16/285,634 US11046724B2 (en) | 2004-09-07 | 2019-02-26 | Methods and compounds for modulating the secretion or expression of adhesion proteins or angiopoietins of cells |
US17/362,028 US20220024961A1 (en) | 2004-09-07 | 2021-06-29 | Methods and compounds for modulating the secretion or expression of adhesion proteins or angiopoietins of cells |
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PCT/US2007/077273 WO2008028060A2 (en) | 2006-09-01 | 2007-08-30 | Anti-tumor compounds for inhibiting cancer growth |
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US12/541,713 Continuation-In-Part US8735558B2 (en) | 2004-09-07 | 2009-08-14 | Blocking the migration or metastasis of cancer cells by affecting adhesion proteins and the uses of new compounds thereof |
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US7514412B2 (en) | 2003-10-09 | 2009-04-07 | Pacific Arrow Limited | Anticancer biangeloyl saponins |
US7524824B2 (en) | 2003-09-04 | 2009-04-28 | Pacific Arrow Limited | Composition comprising Xanthoceras sorbifolia extracts, compounds isolated from same, methods for preparing same and uses thereof |
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US7524824B2 (en) | 2003-09-04 | 2009-04-28 | Pacific Arrow Limited | Composition comprising Xanthoceras sorbifolia extracts, compounds isolated from same, methods for preparing same and uses thereof |
US7514412B2 (en) | 2003-10-09 | 2009-04-07 | Pacific Arrow Limited | Anticancer biangeloyl saponins |
US8614197B2 (en) | 2003-10-09 | 2013-12-24 | Pacific Arrow Limited | Anti-tumor compounds with angeloyl groups |
US8841265B2 (en) | 2003-10-09 | 2014-09-23 | Pacific Arrow Limited | Composition comprising triterpene saponins and compounds with angeloyl functional group, methods for preparing same and uses thereof |
US8586719B2 (en) | 2005-04-27 | 2013-11-19 | Pacific Arrow Limited | Triterpenes for modulating gene expression and cell membrane, and as antiprotozoal agents |
US8785405B2 (en) | 2010-07-16 | 2014-07-22 | Pacific Arrow Limited | Compounds for treating cancer and other diseases |
US11591599B2 (en) | 2013-03-15 | 2023-02-28 | Fundació Institut De Recerca Biomèdica (Irb Barcelona) | Method for the diagnosis, prognosis and treatment of cancer metastasis |
EP3272880A3 (en) * | 2013-03-15 | 2018-04-11 | Fundació Institut de Recerca Biomèdica IRB (Barcelona) | Method for the diagnosis, prognosis and treatment of metastatic cancer |
CN103235141A (en) * | 2013-04-27 | 2013-08-07 | 上海交通大学医学院附属新华医院 | Application of ATF (activating transcription factor) 3 to predicting bladder cancer metastasis and judging prognosis |
US10793642B2 (en) | 2014-12-11 | 2020-10-06 | Inbiomotion S.L. | Binding members for human c-MAF |
KR102128331B1 (en) * | 2018-04-30 | 2020-06-30 | 인하대학교 산학협력단 | Composition for suppressing cancer metastasis into aged vascular endothelial cell by radiation-induced, comprising suppressor of CDH13 or gene encoding the same |
KR20190125819A (en) * | 2018-04-30 | 2019-11-07 | 인하대학교 산학협력단 | Composition for suppressing cancer metastasis comprising suppressor of CDH13 or gene encoding the same |
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AU2008244648A1 (en) | 2008-11-06 |
EP2121715A1 (en) | 2009-11-25 |
CA2676791A1 (en) | 2008-11-06 |
SG178795A1 (en) | 2012-03-29 |
CN101772511A (en) | 2010-07-07 |
EP2121715A4 (en) | 2010-12-29 |
JP2010519219A (en) | 2010-06-03 |
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