CN110974840A - Steroid sulfatase inhibitor and pharmaceutical application thereof - Google Patents
Steroid sulfatase inhibitor and pharmaceutical application thereof Download PDFInfo
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- CN110974840A CN110974840A CN201911372265.3A CN201911372265A CN110974840A CN 110974840 A CN110974840 A CN 110974840A CN 201911372265 A CN201911372265 A CN 201911372265A CN 110974840 A CN110974840 A CN 110974840A
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
The invention discloses a steroid sulfatase inhibitor and can be used for preparing a medicament for preventing and treating diseases caused by abnormal activation of the steroid sulfatase inhibitor. The in vitro enzyme activity inhibition experiment of the inhibitor shows that: the polydatin can inhibit activity of steroid sulfatase, and has good inhibitory effect. Meanwhile, in-vitro cell model killing experiments show that the curative effect of the polydatin on breast cancer cells with high steroid sulfatase expression is obviously better than that of a wild type group and a blank control group. In addition, the results of in vivo animal pharmacodynamics experiments show that polydatin can obviously inhibit the growth activity of breast cancer cells with high steroid sulfatase expression. Therefore, the polydatin medicine can be used as an effective component for preparing the steroid sulfatase inhibitor and can be used for preparing the medicine for preventing and treating diseases (including but not limited to breast cancer) caused by abnormal activation of the enzyme.
Description
Technical Field
The invention belongs to the technical field of medical application, and relates to a steroid sulfatase inhibitor prepared by using polydatin as an active ingredient, which can be used for preventing and treating breast cancer diseases caused by abnormal activation of the enzyme.
Background
Steroid Sulfatase (STS) is an antigen that stimulates the body to produce a specific immune response and binds to the immune response product antibody and sensitized lymphocytes in vitro and in vivo, thereby producing an immune effect (specific reaction). The basic properties of antigens are two, the ability to induce an immune response, i.e. immunogenicity; secondly, it reacts with the products of the immune response, i.e. antigenicity.
In recent years, related researches show that the steroid sulfatase is closely related to breast cancer. The estrogen level in the peripheral circulation of postmenopausal breast cancer patients is obviously reduced, while the estrogen in the breast cancer tissues is still at a higher level, so that the estrogen synthesized by tumor cells per se is probably more important for the postmenopausal breast cancer patients than the estrogen in the peripheral blood in promoting the growth of the tumor cells. Breast cancer tissues can synthesize estrone via the steroid sulfatase (STS) pathway, which in turn produces estradiol. Partial research shows that the expression rate and the activity of STS in breast cancer tissues are obviously improved. Therefore, STS may play a major role in estrogen synthesis in breast cancer tissues[1]. Therefore, the search for STS inhibitors continues and new drugs for preventing and treating breast cancer caused by abnormal activation of STS is under way.
Chinese medicine always plays a significant role in China. In recent years, related experts and scholars continuously separate and extract a series of anti-tumor active ingredients from Chinese herbal medicines, and the anti-tumor active ingredients provide wide application prospects for future research. Polydatin (PD) is prepared from rhizoma Polygoni Cuspidati (Polygonum cuspidatum (L.) Schott of Polygonum of PolygonaceaePolygonum Cuspidatum) The fourth monomer extracted from the dried rhizome of (1), so called Polygonum cuspidatum Crystal No. 4, is abundantly present in grapes and wine. In recent years, some studies of polydatin by relevant scholars at home and abroad show that: the polydatin has remarkable effects in resisting platelet aggregation/thrombosis, enhancing myocardial cell contraction and relaxation function, improving microcirculation of important tissues and organs after shock, etc[2-8](ii) a At the same time, polydatin also has effects of relieving chronic pain caused by endometriosis and improving colitis[9,10]. However, polydatin as STS inhibitor has not been reported to have the effect of preventing and treating breast cancer.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a steroid sulfatase inhibitor which is mainly characterized by taking polydatin as the inhibitor.
The second purpose of the invention is to provide the application of polydatin in preparing medicines for preventing and treating breast cancer diseases caused by abnormal activation of steroid sulfatase, and the medicines are all molecular pathological types of breast cancer containing luminal A, luminal B, HER-2 and triple negative types.
The technical scheme of the invention is summarized as follows:
the use of a steroid sulphatase inhibitor in the manufacture of a medicament for the prevention or treatment of a disease caused by abnormal activation of the enzyme; the steroid sulfatase inhibitor refers to polydatin, and the disease includes, but is not limited to, breast cancer. All molecular pathological types including luminal A, luminal B, HER-2 and tripartite.
The invention further discloses a composition of the steroid sulfatase inhibitor polydatin, which comprises polydatin and one or more pharmaceutically acceptable carriers, excipients or diluents. The composition is mainly in the form of solid oral preparation, liquid oral preparation and injection, wherein the concentration of polydatin is less than or equal to 12.1 mug/ml.
The invention is described in more detail below:
a steroid sulfatase inhibitor is mainly composed of polydatin. In the inhibitor, the concentration of polydatin drug is less than or equal to 12.1 μ g/ml, preferably 12.1 μ g/ml.
The molecular formula of polydatin is C20H22O8(ii) a The structural formula is shown as the formula (I):
(I)。
the polydatin as a steroid sulfatase inhibitor is used for preparing a medicine for preventing and treating breast cancer diseases caused by abnormal activation of steroid sulfatase, including all breast cancer molecular pathological types of luminal A, luminal B, HER-2 and triple negative type.
The invention firstly uses the in vitro enzyme activity inhibition experiment, and the result shows that: the polydatin can inhibit activity of steroid sulfatase, and has good inhibitory effect.
Secondly, in vitro cell model killing experiments show that the curative effect of the polydatin on breast cancer cells with high steroid sulfatase expression is obviously better than that of a wild type group and a blank control group. Meanwhile, the results of in vivo animal pharmacodynamic experiments show that: the polydatin can obviously inhibit the growth activity of breast cancer cells with high expression of steroid sulfatase.
The invention discloses a steroid sulfatase inhibitor which comprises a pharmaceutical composition consisting of polydatin and one or more pharmaceutically acceptable carriers, excipients or diluents. The pharmaceutical composition can be made into solid oral preparation, liquid oral preparation, injection, etc.
The steroid sulfatase inhibitors of the present invention may also be administered parenterally. The preferred form of parenteral administration is injection. The solid and liquid oral formulations comprise: tablets, enteric tablets, capsules, syrups, oral solutions, injections, and the like.
The steroid sulfatase inhibitor pharmaceutical composition of the invention is prepared as follows: the compounds of the present invention are combined with pharmaceutically acceptable solid or liquid carriers and optionally with pharmaceutically acceptable adjuvants and excipients using standard and conventional techniques to prepare microparticles or microspheres. Solid dosage forms include tablets, capsules, sustained release tablets, sustained release pellets and the like. A solid carrier can be at least one substance that can act as a diluent, flavoring agent, solubilizing agent, lubricant, suspending agent, binder, disintegrant, and encapsulating agent. Inert solid carriers include magnesium phosphate, magnesium stearate, powdered sugar, lactose, pectin, propylene glycol, polysorbate 80, dextrin, starch, gelatin, cellulosic materials such as methyl cellulose, microcrystalline cellulose, low melting paraffin, polyethylene glycol, mannitol, cocoa butter, and the like. Liquid dosage forms include solvents, suspensions such as injections, powders, and the like.
Drawings
FIG. 1 inhibitory Effect of polydatin on STS Activity in vitro;
FIG. 2 shows that the polydatin is treated for 24h against human breast cancer cells MDA-MB-231 (wild type), MDA-MB-231 (blank control plasmid overexpression treatment) and MDA-MB-231 (STS plasmid overexpression treatment), and then the survival of each group of cells is observed;
FIG. 3 shows the survival of each group of cells after 24h treatment of polydatin against human breast cancer cells MCF-7 (wild type), MCF-7 (blank control plasmid overexpression treatment), MCF-7 (STS plasmid overexpression treatment);
FIG. 4 shows the tumor size of 15 days after 15 days of administration of polydatin to tumor-bearing mice with human breast cancer cells MDA-MB-231 (wild type), MDA-MB-231 (blank control plasmid overexpression treatment), and MDA-MB-231 (STS plasmid overexpression treatment);
FIG. 5 shows the mean weights of tumors in groups 15 days after administration of polydatin to human breast cancer cells MDA-MB-231 (wild type), MDA-MB-231 (blank control plasmid overexpression treatment) and MDA-MB-231 (STS plasmid overexpression treatment) in tumor-bearing mice for 15 days.
Detailed Description
The invention is described below by means of specific embodiments. Unless otherwise specified, the technical means used in the present invention are well known to those skilled in the art. In addition, the embodiments should be considered illustrative, and not restrictive, of the scope of the invention, which is defined solely by the claims. It will be apparent to those skilled in the art that various changes or modifications in the components and amounts of the materials used in these embodiments can be made without departing from the spirit and scope of the invention. The raw materials and reagents used in the present invention are commercially available. Wherein the polydatin is commercially available:
experimental human STS recombinant protease was purchased from abcam (commercial product);
human-derived breast cancer cells MDA-MB-231 (ATCC HTB-26) are purchased from the American ATCC cell center;
the human breast cancer cell MCF-7 is purchased from the cell resource center of the basic medicine institute of Chinese medical academy of sciences.
The present invention will be further described with reference to specific examples.
Example 1
The molecular formula of polydatin is C20H22O8(ii) a The structural formula is shown as the formula (I):
(I)。
the polydatin is used as an active ingredient, and pharmaceutically acceptable auxiliary materials are added to prepare liquid injections with various specifications by a conventional method.
The administration routes of the polydatin include various routes, such as injection administration, intracavity administration and the like.
(1) Preparation of injection:
polydatin 200 mg, mannitol 700 mg, PEG 300010 mg, and distilled water 100 ml, wherein pH is 7.0-7.5, the concentration of the filtrate is 3mg/ml, 2 ml per ampoule is packaged, and freeze-dried to obtain injection.
(2) Preparation of tablets:
10mg of polydatin, 35 mg of microcrystalline cellulose, 45 mg of starch, 4 mg of polyvinylpyrrolidone, 4.5 mg of sodium carboxymethyl starch, 0.5 mg of magnesium stearate and 1 mg of talcum powder; sieving polydatin active ingredient, starch and cellulose, mixing polyvinylpyrrolidone solution and the above powders, sieving, drying at 50 deg.C to obtain wet granule, sieving carboxymethyl starch sodium salt, magnesium stearate and pulvis Talci, adding into the above granule, and tabletting.
(3) Preparation of capsules
10mg of polydatin crystal form, respectively sieving the active ingredient and the auxiliary materials with a 100-mesh sieve, weighing the main medicine and the auxiliary materials according to the prescription amount, fully mixing, adding a proper amount of hydroxypropyl methylcellulose solution to prepare a soft material, sieving with a 24-mesh sieve, drying the prepared wet granules in an oven at 50-60 ℃ for about 2-3 hours, uniformly mixing magnesium stearate and talcum powder with the granules, grading, measuring the content of an intermediate, and filling with No. 2 capsules.
Example 2
The effect of polydatin on the in vitro inhibition of steroid sulfatase.
We have found that polydatin has obvious inhibition effect on the activity of human steroid sulfatase by using polydatin drug solution to act on the human steroid sulfatase in vitro, and particularly has very good inhibition effect on the steroid sulfatase when the concentration of the polydatin drug is less than or equal to 12.1 mu g/ml, thereby suggesting that the polydatin can be used as an active ingredient to prepare the steroid sulfatase inhibitor. The results are shown in detail in FIG. 1.
Note: the abnormal activation expression of steroid sulfatase currently exists widely in the initiation of breast cancer diseases. Because the existing inhibitor drugs for inhibiting the abnormal activation of steroid sulfatase are few, and most of the drugs are chemically synthesized drugs, the toxic and side effects are large, and the price and the cost are high. Therefore, the low-toxicity and cheap traditional Chinese medicine component, namely the polydatin, is expected to be used as an active component to develop and treat the breast cancer diseases caused by abnormal activation of steroid sulfatase.
Example 3
And comparing the inhibition effect of polydatin on the activity of each group of cells of human breast cancer cell models MDA-MB-231 and MCF-7.
Six human breast cancer cell lines including MDA-MB-231 (blank control plasmid overexpression treatment), MDA-MB-231 (STS plasmid overexpression treatment), MDA-MB-231 (wild type), MCF-7 (blank control plasmid overexpression treatment), MCF-7 (STS plasmid overexpression treatment) and MCF-7 (wild type) constructed and screened in the laboratory are respectively plated by using 96-hole cell culture plates according to the number of 5000 cells per hole, after the cells adhere to the wall, adding polydatin (10 μ g/ml, 20 μ g/ml) medicinal liquid with different concentrations, continuously culturing for 24 times, absorbing the original waste liquid, adding a certain amount of culture medium containing CCK-8 reagent into each well, continuously incubating at 37 deg.C for 1h, and reading absorbance at wavelength of 450nm with enzyme-labeling instrument. The experimental results show that: the inhibitory effect of polydatin with different concentrations on two human breast cancer cell models MDA-MB-231 (STS plasmid overexpression treatment) and MCF-7 (STS plasmid overexpression treatment) is better than that of respective wild type and blank control groups, so that the good special effect specificity of polydatin in treating breast cancer tumor diseases with STS high expression abnormal types is obviously embodied. The detailed results are shown in fig. 2 and 3.
Example 4
The effect of polydatin on the therapeutic effect of tumor cell tumor-bearing mice with human-derived breast cancer cells MDA-MB-231 (wild type), MDA-MB-231 (blank control plasmid overexpression treatment), and MDA-MB-231 (STS plasmid overexpression treatment) was compared.
Three human breast cancer cell lines including MDA-MB-231 (blank control plasmid overexpression treatment), MDA-MB-231 (STS plasmid overexpression treatment) and MDA-MB-231 (wild type) constructed and screened in the laboratory are inoculated under Balb/c skin of an immunodeficient mouse according to the number of two million cells inoculated per point, and the mouse is divided into three experimental groups. Three groups of mice were administered with polydatin (100 mg/kg) by intraperitoneal injection once a day after the mice developed macroscopic tumor mass subcutaneously for about two weeks. At the end of the experiment on day 15, all mice were sacrificed and the tumors were photographed and weighed.
We found again by in vivo efficacy experiments in mice: the inhibitory effect of polydatin on breast cancer tumor cells with STS overexpression is much better than that of the corresponding wild type group and blank plasmid expression control group, which is consistent with the results of previous in vitro experiments. The detailed results are shown in fig. 4 and 5.
The main references:
1. Reed lv U, Purohit A, Woo LW, et a1. Steroid sulfamse: molecularbiology, regulation, and inhibition. Endocr Rev, 2005, 26(2):171-202.
2. Gao JP, Chen CX, Gu WL, et al. Effects of polydatin on attenuatingventricular remodeling in isoproterenol-induced mouse and pressure-overload rat models. Fitoterapia.2010;81(7):953-960.
3. Zhang LP, Ma HJ, Bu HM, et al. Polydatin attenuates ischemia/reperfusion-induced apoptosis in myocardium of the rat. Sheng Li XueBao.2009;61:367-72.
4. Zhang PW, Yu CL, Wang YZ, et al. Influence of 3,4,5-trihydroxystibene-3-beta-mono-D-
glucoside on vascular endothelial epoprostenol and plateletaggregation. Acta Pharmacologica Sinica.1995;16:265–268.
5. Wang X, Song R, Chen Y et al. Polydatin-a new mitochondria protectorfor acute severe hemorrhagic shock treatment. Expert Opin InvestigDrugs.2013;22(2):169-179.
6. Wang X, Song R, Bian HN, et al. Polydatin, a natural polyphenol,protects arterial smooth muscle cells against mitochondrial dysfunctionand lysosomal destabilization following hemorrhagic shock. Am JPhysiol Regul Integr Comp Physiol.2012;302(7):R805-814.
7. Cheng Y, Zhang HT, Sun L, et al. Involvement of cell adhesionmolecules in polydatin protection of brain tissues from ischemia-reperfusion injury. Brain Res. 2006;1110(1):193-200.
8. Miao Q, Wang S, Miao S, et al. Cardioprotective effect of polydatinagainst ischemia/reperfusion injury: roles of protein kinase C and mito K(ATP) activation. Phytomedicine. 2011;19(1):8-12.
9. Indraccolo U, Barbieri F. Effect of palmitoylethanolamide-polydatincombination on chronic pelvic pain associated with endometriosis: preliminaryobservations. Eur J Obstet Gynecol Reprod Biol.2010;150(1):76-79.
10. Yao J, Wang JY, Liu L, et al. Polydatin ameliorates DSS-inducedcolitis in mice through inhibition of nuclear factor-kappa B activation.Planta Med.2011;77(5):421-427。
Claims (4)
1. the use of a steroid sulphatase inhibitor in the manufacture of a medicament for the prevention or treatment of a disease caused by abnormal activation of the enzyme; the steroid sulfatase inhibitor refers to polydatin, and the disease includes, but is not limited to, breast cancer.
2. The breast cancer of claim 1, which is: all molecular pathological types including luminal A, luminal B, HER-2 and tripartite.
3. A composition comprising the steroid sulfatase inhibitor polydatin of claim 1, wherein said composition comprises polydatin in combination with one or more pharmaceutically acceptable carriers, excipients, or diluents.
4. The pharmaceutical composition of claim 3, wherein the dosage form is a solid oral preparation, a liquid oral preparation, an injection; the concentration of the polydatin medicine is less than or equal to 12.1 mug/ml.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2000038341A (en) * | 1991-08-29 | 2000-02-08 | Imperial College Of Science Technol & Medicine | Steroid sulfatase inhibitor |
| CN108159061A (en) * | 2018-03-02 | 2018-06-15 | 天津市肿瘤医院 | Polygonin paclitaxel composition and the purposes in preparation prevention stomach malignant tumor medicine |
| CN109045050A (en) * | 2018-09-10 | 2018-12-21 | 天津市肿瘤医院 | Polygonin paclitaxel composition and purposes |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2000038341A (en) * | 1991-08-29 | 2000-02-08 | Imperial College Of Science Technol & Medicine | Steroid sulfatase inhibitor |
| CN108159061A (en) * | 2018-03-02 | 2018-06-15 | 天津市肿瘤医院 | Polygonin paclitaxel composition and the purposes in preparation prevention stomach malignant tumor medicine |
| CN109045050A (en) * | 2018-09-10 | 2018-12-21 | 天津市肿瘤医院 | Polygonin paclitaxel composition and purposes |
Non-Patent Citations (2)
| Title |
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| BOYU PAN，等: "Uncovering the action mechanism of polydatin via network pharmacological target prediction", RSC ADVANCES, vol. 8, no. 34, pages 18852 * |
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