WO2002067964A1 - Compositions and methods for cancer prevention and treatment derived from $i(inula britannica) - Google Patents
Compositions and methods for cancer prevention and treatment derived from $i(inula britannica) Download PDFInfo
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- WO2002067964A1 WO2002067964A1 PCT/US2002/004891 US0204891W WO02067964A1 WO 2002067964 A1 WO2002067964 A1 WO 2002067964A1 US 0204891 W US0204891 W US 0204891W WO 02067964 A1 WO02067964 A1 WO 02067964A1
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- Inula bri tannica is a traditional Chinese medicinal herb that has been used to treat bronchitis and inflammation.
- a variety of this plant, known as Inula bri tannica chinensis has been used as an insecticide in certain areas of China.
- Both Inula bri tannica and Inula bri tannica chinensis have been examined in order to determine the chemical constituents responsible for its pharmacological effects.
- a variety of sesquiterpenes have been isolated.
- Bcl-2 acts by inducing Bcl-2 phosphorylation in cancer cells which leads to programmed cell death (Haldar, S. Et al . 1996. Cancer Res . 56:1253-1255) .
- the Bcl-2 protein is a member of a family of cytoplasmic proteins which regulates cell death. Bcl-2 has been shown to promote cell survival by inhibiting the process of cell death known as apoptosis.
- Bcl-2 acts to inhibit apoptosis
- Bax another cytoplasmic protein
- Bcl-2 is also thought to protect cells from apoptosis by dimerizing with Bax (Hunter, J.J. et al. 1996. J. Biol . Chew. 271:8521-8524).
- the phosphorylation of Bcl-2 interferes with the homodimers and subsequent apoptosis (Haldar, S. et al . 1995. Proc . Natl . Acad. Sci . USA 92:4507-4511; Haldar, S. Et al . 1996. Cancer Res . 56:1253-1255).
- An object of the present invention is a composition that induces apoptosis in cells which comprises an extract of Inula Bri tannica or compounds isolated therefrom.
- the composition comprises sesquiterpene lactone.
- Another object of the present invention is a method for inducing apoptosis in cells comprising contacting cells with an extract of Inula Bri tannica or compounds isolated therefrom so that apoptosis is induced.
- Yet another object of the present invention is a method for preventing and treating cancer which comprises administering an effective amount of extract of Inula Bri tannica or compounds isolated therefrom.
- An extract of Inula bri tannica has been isolated that has use as a cancer preventative agent due to its activity to induce apoptosis in cancer cells.
- the extract contains several sesquiterpene compounds, including but not limited to the sesquiterpene lactones known as britannilactone, 1-0- acetylbritannilactone (OABL), and 1,6-0,0- diacetylbritannilactone (OODABL) .
- the extract and the chemicals isolated therefrom can be used as a pharmaceutical for cancer treatment and/or prevention as well as a medical food, or nutraceutical, and a dietary supplement.
- the chloroform-soluble fraction of the ethanol extract (500 g) was chromatographed on a silica gel column eluting with a gradient of chloroform-methanol . From the fraction collected with chloroform-methanol (20:1), 1,6-0,0- diacetylbritannilactone (52 g) was obtained. From the fraction collected with chloroform-methanol (10:1), 1-0- acetylbritannilactone (10.5 g) was obtained.
- compositions of the present invention were tested in PA-1 ovary cells.
- PARP is a 116 kD nuclear poly (ADP- ribose)polymerase that appears to be involved in DNA-repair, predominantly in response to environmental stress (Satoh, M.S. and T. Lindahl. 1992. Nature 356:356-358).
- PARP is important for cells to maintain their viability. Cleavage of PARP facilitates cellular disassembly and serves as a marker of cells undergoing apoptosis (Oliver, F.J. et al . 1998. J “ . Biol . Chem. 273:33533-33539) . This protein can be cleaved by many ICE caspases to form a 85 kD protein in cells undergoing apoptosis. PA-1 cells were treated with OODABL for 24 hours. Cells were lysed and PARP cleavage was measured by Western Blot using a monoclonal antibody to PARP (Pharmingen, Inc., San Dieago, CA) . OABL induced PARP cleavage at doses of 10 and 20 ⁇ M, while OODABL induced PARP cleavage at a dose of 5 ⁇ M.
- OODABL arrested cells at the G2/M phase at a 20 ⁇ M concentration as compared to control cells.
- OODABL polymerized microtubules like paclitaxel .
- apoptosis was examined.
- HL-60 cells lines were subjected to flow cytometry analysis using APO-BRDU.
- Apoptosis was detected by incorporation of Br-dUTP using a fluorescein labeled anti-BrdU monoclonal antibody after treatment with a vehicle control, 1 ⁇ M camptothecin or 20 ⁇ M OODABL for 12 hours.
- OODABL was shown to induce apoptosis, as did the positive control camptothecin.
- Cell viability was then assessed in a microculture tetrazolium/formazan assay (MTT; Scudiero, D.A. et al . 1988. Cancer Res .
- MTT microculture tetrazolium/formazan assay
- NCI-H-460 cell treated with various concentrations of OODABL (3.9, 7.81, l 5.62, 31.25, 62.5 and 125 ⁇ M OODABL)
- cell viability was decreased in a dose-dependent manner with an IC 50 of between 31.25 and 62.5 ⁇ M.
- NIH 3T3 normal mouse fibroblasts
- OABL was then tested in some of these same cell lines.
- MCF-7 cells OABL was tested at doses of 0.3 nm, 3 nm, 30 nm, 300 nm, 3 ⁇ M, and 30 ⁇ M. Results showed that OABL decreased cell viability with an IC 50 of around 200 ⁇ M.
- OABL (1.953, 3.9, 7.815, 15.62, 31.25 and 62.5 ⁇ M) decreased cell viability with an IC 50 of about 2 ⁇ M.
- OABL (4.68, 9.37, 18.75, 37.5, 75 and 100 ⁇ M) decreased cell viability.
- Cell cytotoxicity was also assessed by a clonogenic assay.
- MCF-7 breast cells were treated with various concentrations of OODABL (625 nm, 1.25, 2.5, 5 and 10 ⁇ M) for 15 days and cells were then stained with methylene blue and colonies counted.
- the IC 50 was in the range of 2.5 to 5 ⁇ M OODABL.
- PC-3 prostate cells were treated with various concentrations of OODABL (20 and 200 nm, and 2 and 20 ⁇ M) for 15 days and cells were then stained with methylene blue and colonies counted.
- the IC 50 was in the range of 200 nm OODABL.
- RKO cells were treated with various concentrations of OODABL
- IC 50 was in the range of 20 ⁇ M OODABL.
- Baby rat kidney cells were transformed with E1A and transfected with the Bcl-2 gene to form BRK-4B-Bcl-2 cells. These cells were treated with various concentrations of OODABL (20 and 200 nm, and 2, 10 and 20 ⁇ M) for 15 days and cells were then stained with methylene blue and colonies counted.
- the IC 50 was in the range of 200 nM OODABL.
- Baby rat kidney cells were transformed with E1A and transfected with Bcl-2 gene in which phosphorylation sites were mutated to form phosphomutant BRK-4B-Bcl-2 cells. These cells were treated with various concentrations of OODABL (20 and 200 nm, and 2 and 20 ⁇ M) for 15 days and cells were then stained with methylene blue and colonies counted.
- the IC 50 was in the range of 2 ⁇ M.
- the level of Bcl-2 phosphorylation was then assessed in the non-mutated and mutated BRK-4B-Bcl-2 cells using a Western blot assay.
- Cells were initially treated for 12 hours with the test compound, OODABL (at concentrations of 10, 20, 30, 40, or 60 ⁇ M) .
- Taxol was used as a positive control at a concentration of 5 ⁇ M.
- Cells were then lysed in ice cold radio-immune precipitation buffer with inhibitors. Equivalent amounts of proteins were electrophoresed by 12% dodecyl sulfate-polyacrylamide gel electrophoresis and transferred to nitrocellulose.
- Bcl-2 and phosphorylated Bcl-2 proteins were detected using a monoclonal Bcl-2 primary antibody and a secondary goat anti-mouse horseradish peroxidase conjugated antibody followed by enhanced chemiluminescence detection.
- the results showed that there was a dose-dependent increase in Bcl-2 phosphorylation with OODABL in the non-mutated cells.
- Taxol also produced an increased in protein phosphorylation. In the mutated rat kidney cells, there was no phosphorylation evident with either taxol or OODABL .
- compositions of the present invention would be useful as nutraceuticals for prevention or treatment of cancer.
- One of skill would be able to use the results of experiments in cells and animals to determine an effective amount to be administered in humans.
- An effective amount would be an amount that induces apoptosis or inhibits tumor growth either in vi tro or in vivo in animals.
- human test doses can be extrapolated from effective doses in cell studies, such as IC 50 values, or from effective doses in vivo by extrapolating on a body weight or surface area basis.
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Abstract
Compositions and methods for preventing and treating cancer are provided that comprise extracts of Inula britannica or compounds isolated therefrom.
Description
COMPOSITIONS AND METHODS FOR CANCER PREVENTION AND TREATMENT DERIVED FROM INULA BRITANNICA
Introduction
This application claims the benefit of priority from U.S. provisional application Serial No. 60/270,189, filed February 21, 2001.
Background of the Invention
Inula bri tannica is a traditional Chinese medicinal herb that has been used to treat bronchitis and inflammation. A variety of this plant, known as Inula bri tannica chinensis has been used as an insecticide in certain areas of China. Both Inula bri tannica and Inula bri tannica chinensis have been examined in order to determine the chemical constituents responsible for its pharmacological effects. A variety of sesquiterpenes have been isolated. In the case of Inula bri tannica chinensis, three specific sesquiterpene lactones were identified, including britannilactone, 1-0- acetylbritannilactone, and 1, 6-0, 0-diacetylbritannilactone
(Zhou, B-N. et al . 1993. Phytochemistry 34:249-252). Some natural plant extracts have been shown to have activity as chemopreventive agents. An example, taxol, acts by inducing Bcl-2 phosphorylation in cancer cells which leads to programmed cell death (Haldar, S. Et al . 1996. Cancer Res . 56:1253-1255) . The Bcl-2 protein is a member of a family of cytoplasmic proteins which regulates cell death. Bcl-2 has been shown to promote cell survival by inhibiting the process of cell death known as apoptosis. Whereas Bcl-2 acts to inhibit apoptosis, Bax, another cytoplasmic protein, counteracts this protective effect; Bcl-2 is also thought to
protect cells from apoptosis by dimerizing with Bax (Hunter, J.J. et al. 1996. J. Biol . Chew. 271:8521-8524). The phosphorylation of Bcl-2 interferes with the homodimers and subsequent apoptosis (Haldar, S. et al . 1995. Proc . Natl . Acad. Sci . USA 92:4507-4511; Haldar, S. Et al . 1996. Cancer Res . 56:1253-1255). Therefore, therapeutic strategies to inactivate Bcl-2 are being sought as a way to improve clinical results with certain drugs. It has now been found that an extract of Inula bri tannica has activity relevant to prevention and treatment of cancer due to its activity to phosphorylate Bcl-2.
Summary of the Invention
An object of the present invention is a composition that induces apoptosis in cells which comprises an extract of Inula Bri tannica or compounds isolated therefrom. In a preferred embodiment the composition comprises sesquiterpene lactone.
Another object of the present invention is a method for inducing apoptosis in cells comprising contacting cells with an extract of Inula Bri tannica or compounds isolated therefrom so that apoptosis is induced.
Yet another object of the present invention is a method for preventing and treating cancer which comprises administering an effective amount of extract of Inula Bri tannica or compounds isolated therefrom.
Detailed Description of the Invention
An extract of Inula bri tannica has been isolated that has use as a cancer preventative agent due to its activity to induce apoptosis in cancer cells. The extract contains several sesquiterpene compounds, including but not limited to the sesquiterpene lactones known as britannilactone, 1-0- acetylbritannilactone (OABL), and 1,6-0,0- diacetylbritannilactone (OODABL) . The extract and the
chemicals isolated therefrom can be used as a pharmaceutical for cancer treatment and/or prevention as well as a medical food, or nutraceutical, and a dietary supplement.
The flowers (approximately 10 kg) of Inula bri tannica var. chinensis were extracted three times with 95% ethanol . The chloroform-soluble fraction of the ethanol extract (500 g) was chromatographed on a silica gel column eluting with a gradient of chloroform-methanol . From the fraction collected with chloroform-methanol (20:1), 1,6-0,0- diacetylbritannilactone (52 g) was obtained. From the fraction collected with chloroform-methanol (10:1), 1-0- acetylbritannilactone (10.5 g) was obtained.
Experiments were performed to determine the activity of two of the sesquiterpene compounds isolated from Inula bri tannica, OABL and OODABL, as cancer preventative agents. Using a Western blot technique, the ability of these compounds to phosphorylate Bcl-2 in cancer cells was examined. Using the breast cancer cell line MCF-7, it was found that OABL induced Bcl-2 phosphorylation, with effective doses of 10 and 20 μM. OODABL induced Bcl-2 phosphorylation at lower effective doses, 2.5 and 5 μM. These results were compared to the ability of a known chemotherapeutic paclitaxel, which induced Bcl-2 phosphorylation at a dose of 100 μM. These data indicate that the sesquiterpenes are more potent than paclitaxel at inducing Bcl-2 phosphorylation in MCF-7 cells. In two ovarian cancer cell lines, OVCAR and PA-1, similar results were seen. In OVCAR cells, OODABL induced Bcl-2 phosphorylation at a dose of 5 μM, while OABL induced Bcl-2 phosphorylation at a dose of 10 μM. In PA-1 cells, OODABL induced Bcl-2 phosphorylation at a dose of 5 μM, while
OABL induced Bcl-2 phosphorylation at a dose of 10 μM.
In a prostate cancer cell line, these compounds were also able to induce Bcl-2 phosphorylation. OODABL induced Bcl-2 phosphorylation at a dose of 5 μM while OABL induced Bcl-2 phosphorylation at a dose of 10 μM.
Using cleavage of PARP as an indicator of apoptosis , the compositions of the present invention were tested in PA-1 ovary cells. PARP is a 116 kD nuclear poly (ADP- ribose)polymerase that appears to be involved in DNA-repair, predominantly in response to environmental stress (Satoh, M.S. and T. Lindahl. 1992. Nature 356:356-358). PARP is important for cells to maintain their viability. Cleavage of PARP facilitates cellular disassembly and serves as a marker of cells undergoing apoptosis (Oliver, F.J. et al . 1998. J". Biol . Chem. 273:33533-33539) . This protein can be cleaved by many ICE caspases to form a 85 kD protein in cells undergoing apoptosis. PA-1 cells were treated with OODABL for 24 hours. Cells were lysed and PARP cleavage was measured by Western Blot using a monoclonal antibody to PARP (Pharmingen, Inc., San Dieago, CA) . OABL induced PARP cleavage at doses of 10 and 20 μM, while OODABL induced PARP cleavage at a dose of 5 μM.
The effect of OODABL on cell cycle was analyzed by flow cytometery using breast cancer cell lin T47D. OODABL arrested cells at the G2/M phase at a 20 μM concentration as compared to control cells.
The effect of OODABL on microtubules was examined by indirect immunofluorescence of MCF-7 cells using an antibody to tubulin after 12 hours treatment with either a vehicle control, 10 μM paclitaxel (positive control) , or 20 μM OODABL. The results showed, that OODABL polymerized microtubules like paclitaxel .
In a TUNEL assay, the effect of OODABL on late apoptosis was examined. HL-60 cells lines were subjected to flow cytometry analysis using APO-BRDU. Apoptosis was detected by incorporation of Br-dUTP using a fluorescein labeled anti-BrdU monoclonal antibody after treatment with a vehicle control, 1 μM camptothecin or 20 μM OODABL for 12 hours. OODABL was shown to induce apoptosis, as did the positive control camptothecin.
Cell viability was then assessed in a microculture tetrazolium/formazan assay (MTT; Scudiero, D.A. et al . 1988. Cancer Res . 48:4827-4833) using a variety of cell lines. Absorbance was measured at 550 nm and cell viability was expressed as the percentage of drug treated cells relative to that of controls . The ICS0 was then defined as the concentration of drug that produced a 50% decrease in cell viability relative to controls. OODABL was first tested in a variety of cell lines. Results in MCF-7 cells treated with various concentrations of OODABL (1.25, 12.5, 25. 50 and 100 μM OODABL) showed that cell viability decreased with treatment in a dose-dependent manner. The IC50 was less than 12.5 μM. In PA-1 cells treated with various concentrations of OODABL (1.953, 3.9, 7.815, 15.625, 31.25, and 62.5 μM OODABL), cell viability was decreased in a dose-dependent manner with an IC50 of less than 7.815 μM. In DU-145 cells treated with various concentrations of OODABL (3.4, 7.86, 15.6, 31.5, 62.5, and 125 μM OODABL) , cell viability was decreased in a dose-dependent manner with an IC50 of less than 15.6 μM. In NCI-H-460 cell treated with various concentrations of OODABL (3.9, 7.81, l 5.62, 31.25, 62.5 and 125 μM OODABL), cell viability was decreased in a dose-dependent manner with an IC50 of between 31.25 and 62.5 μM. In NIH 3T3 (normal mouse fibroblasts) cells treated with various concentrations of OODABL (1, 10, 20 and 50 μM OODABL) , cell viability was decreased in a dose- dependent manner with an IC50 of 50 μM.
OABL was then tested in some of these same cell lines. In MCF-7 cells, OABL was tested at doses of 0.3 nm, 3 nm, 30 nm, 300 nm, 3 μM, and 30 μM. Results showed that OABL decreased cell viability with an IC50 of around 200 μM. In PA- 1 cells, OABL (1.953, 3.9, 7.815, 15.62, 31.25 and 62.5 μM) decreased cell viability with an IC50 of about 2 μM. In Du-145 cells, OABL (4.68, 9.37, 18.75, 37.5, 75 and 100 μM) decreased cell viability.
Cell cytotoxicity was also assessed by a clonogenic assay. MCF-7 breast cells were treated with various concentrations of OODABL (625 nm, 1.25, 2.5, 5 and 10 μM) for 15 days and cells were then stained with methylene blue and colonies counted. The IC50 was in the range of 2.5 to 5 μM OODABL. PC-3 prostate cells were treated with various concentrations of OODABL (20 and 200 nm, and 2 and 20 μM) for 15 days and cells were then stained with methylene blue and colonies counted. The IC50 was in the range of 200 nm OODABL. RKO cells were treated with various concentrations of OODABL
(20 and 200 nm, and 2 and 20 μM) for 15 days and cells were then stained with methylene blue and colonies counted. The
IC50 was in the range of 20 μM OODABL. Baby rat kidney cells were transformed with E1A and transfected with the Bcl-2 gene to form BRK-4B-Bcl-2 cells. These cells were treated with various concentrations of OODABL (20 and 200 nm, and 2, 10 and 20 μM) for 15 days and cells were then stained with methylene blue and colonies counted. The IC50 was in the range of 200 nM OODABL. Baby rat kidney cells were transformed with E1A and transfected with Bcl-2 gene in which phosphorylation sites were mutated to form phosphomutant BRK-4B-Bcl-2 cells. These cells were treated with various concentrations of OODABL (20 and 200 nm, and 2 and 20 μM) for 15 days and cells were then stained with methylene blue and colonies counted. The IC50 was in the range of 2 μM.
The level of Bcl-2 phosphorylation was then assessed in the non-mutated and mutated BRK-4B-Bcl-2 cells using a Western blot assay. Cells were initially treated for 12 hours with the test compound, OODABL (at concentrations of 10, 20, 30, 40, or 60 μM) . Taxol was used as a positive control at a concentration of 5 μM. Cells were then lysed in ice cold radio-immune precipitation buffer with inhibitors. Equivalent amounts of proteins were electrophoresed by 12% dodecyl sulfate-polyacrylamide gel electrophoresis and transferred to nitrocellulose. Bcl-2 and phosphorylated Bcl-2 proteins were
detected using a monoclonal Bcl-2 primary antibody and a secondary goat anti-mouse horseradish peroxidase conjugated antibody followed by enhanced chemiluminescence detection. The results showed that there was a dose-dependent increase in Bcl-2 phosphorylation with OODABL in the non-mutated cells. Taxol also produced an increased in protein phosphorylation. In the mutated rat kidney cells, there was no phosphorylation evident with either taxol or OODABL .
These data demonstrate that the extract of Inula bri tannica has use as a cancer preventative and treatment agent due to its activity to induce apoptosis and cell cytotoxicity in cancer cells. The extract and the chemicals isolated therefrom, OABL and OODABL, can be used as a pharmaceutical for cancer treatment and/or prevention as well as a medical food, or nutraceutical, and a dietary supplement.
The data presented support the development of either foods for animal consumption, where animals include humans, or as dietary supplements for animals including humans . These foods and supplements are referred to by those of skill in the art as "nutraceuticals" . Compositions of the present invention would be useful as nutraceuticals for prevention or treatment of cancer. One of skill would be able to use the results of experiments in cells and animals to determine an effective amount to be administered in humans. An effective amount would be an amount that induces apoptosis or inhibits tumor growth either in vi tro or in vivo in animals. For example, human test doses can be extrapolated from effective doses in cell studies, such as IC50 values, or from effective doses in vivo by extrapolating on a body weight or surface area basis. Such extrapolations are routine in the art. Further, one of skill would know how to formulate or prepare diets or dietary supplements containing the analogs. In the case of animal diets, the analogs could be added in concentrations up to 5% by weight and mixed according to methods routine in the art.
Dietary supplements for animals or humans could be prepared in a variety of forms that would include but not be limited to liquid, powder, or solid pill forms. Pill forms for the supplements would be prepared by methods routine in the art of dosage formulation and could include but not be limited to production of gel capsules, time-release capsules, or solid pills formulated with excipients and binders. Again, one of skill in the art would know how to formulate the extracts or compounds isolated therefrom based on its chemical nature and the desired effect. The extract and/or the compounds isolated therefrom could also be administered topically in liquid or creme of lotion forms or by injection. Injectable forms would be prepared by solubilizing in a pharmaceutically acceptable vehicle.
Claims
1. A composition that induces apoptosis in cells comprising an extract of Inula bri tannica or compounds isolated therefrom.
2. The composition of claim 1 wherein the isolated compound comprises sesquiterpene lactone.
3. The composition of claim 2 wherein the sesquiterpene lactone is 1-O-acetylbritannilactone or 1,6-0,0- diacetylbritannilactone .
4. The composition of claim 1 further comprising a pharmaceutically acceptable vehicle.
5. A method for inducing apoptosis in cells comprising contacting cells with the composition of claim 1.
6. A method for preventing or treating cancer in an animal comprising administering to an animal an effective amount of the composition of claim 1.
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EP02719016A EP1381378A4 (en) | 2001-02-21 | 2002-02-20 | Compositions and methods for cancer prevention and treatment derived from inula britannica |
CA002438932A CA2438932A1 (en) | 2001-02-21 | 2002-02-20 | Compositions and methods for cancer prevention and treatment derived from inula britannica |
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US27018901P | 2001-02-21 | 2001-02-21 | |
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WO2008134474A2 (en) | 2007-04-27 | 2008-11-06 | The Board Of Trustees Of The University Of Illinois | Compositions and methods including cell death inducers and procaspase activation |
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WO2014069692A1 (en) * | 2012-10-31 | 2014-05-08 | 주식회사 한국전통의학연구소 | Composition for treating renal cancer and functional health food containing inula britannica var. chinensis extract |
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US5853727A (en) * | 1996-07-26 | 1998-12-29 | Agrogne Ltd. | Preparation and use of inula extracts as a fungicide for the control of plant diseases |
US6051565A (en) * | 1997-04-26 | 2000-04-18 | International Phytochemistry Research Labs, Ltd. | Farnesyl-protein transferase inhibitors |
US5902809A (en) * | 1997-07-03 | 1999-05-11 | Paracure, Inc. | Arglabin compounds and therapeutic uses thereof |
DE19814404A1 (en) * | 1998-03-31 | 1999-10-07 | Georgios Pandalis | Treatment of malignant tumors with herbal product |
KR100718424B1 (en) * | 1999-12-22 | 2007-05-14 | 엑손모빌 케미칼 패턴츠 인코포레이티드 | Polypropylene-based adhesive compositions |
WO2002067964A1 (en) * | 2001-02-21 | 2002-09-06 | Rutgers, The State University Of New Jersey | Compositions and methods for cancer prevention and treatment derived from $i(inula britannica) |
-
2002
- 2002-02-20 WO PCT/US2002/004891 patent/WO2002067964A1/en not_active Application Discontinuation
- 2002-02-20 EP EP02719016A patent/EP1381378A4/en not_active Withdrawn
- 2002-02-20 CA CA002438932A patent/CA2438932A1/en not_active Abandoned
- 2002-02-20 US US10/079,038 patent/US6627623B2/en not_active Expired - Fee Related
-
2003
- 2003-09-15 US US10/663,530 patent/US20040052881A1/en not_active Abandoned
Non-Patent Citations (3)
Title |
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PARK ET AL.: "Cytotoxic sesquiterpene lactones from inula Britannica", PLANTA MEDICA, vol. 64, no. 8, 1998, pages 752 - 754, XP002950599 * |
See also references of EP1381378A4 * |
ZHOU ET AL.: "Sesquiterpene lactones from inula Britannica", PHYTOCHEMISTRY, vol. 34, no. 1, 1993, pages 249 - 252, XP002950598 * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007109119A2 (en) * | 2006-03-17 | 2007-09-27 | Rutgers, The State University Of New Jersey | Neobritannilactone b and acetyl neobritannilactone b |
WO2007109119A3 (en) * | 2006-03-17 | 2007-11-15 | Univ Rutgers | Neobritannilactone b and acetyl neobritannilactone b |
CN103565985A (en) * | 2013-11-06 | 2014-02-12 | 陈兴日 | Traditional Chinese medicinal composition for treating breast pain and using method thereof |
CN105300278A (en) * | 2014-06-10 | 2016-02-03 | 约翰内斯·海德汉博士有限公司 | Optical positioning device |
CN105300278B (en) * | 2014-06-10 | 2018-10-23 | 约翰内斯·海德汉博士有限公司 | Optical position measuring device |
Also Published As
Publication number | Publication date |
---|---|
US20040052881A1 (en) | 2004-03-18 |
EP1381378A4 (en) | 2004-07-28 |
EP1381378A1 (en) | 2004-01-21 |
US6627623B2 (en) | 2003-09-30 |
CA2438932A1 (en) | 2002-09-06 |
US20020155178A1 (en) | 2002-10-24 |
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