CN116370642A - Application of stephanine hydrochloride-containing drug combination in treatment of prostate cancer - Google Patents
Application of stephanine hydrochloride-containing drug combination in treatment of prostate cancer Download PDFInfo
- Publication number
- CN116370642A CN116370642A CN202310413042.7A CN202310413042A CN116370642A CN 116370642 A CN116370642 A CN 116370642A CN 202310413042 A CN202310413042 A CN 202310413042A CN 116370642 A CN116370642 A CN 116370642A
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- China
- Prior art keywords
- stephanine
- hydrochloride
- androgen receptor
- prostate cancer
- combination
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
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Abstract
The invention discloses an application of a medicine combination containing stephanine hydrochloride in treating prostate cancer. The drug combination comprises the following substances as active ingredients: stephanine hydrochloride and androgen receptor inhibitors. To date, the combination of stephanine and androgen receptor inhibitor, the combination dosage and the medicine proportion have not been reported yet. The scheme of the invention skillfully combines the two for the first time, and the combination of the stephanine hydrochloride and the androgen receptor inhibitor can achieve the effect of remarkably treating castration resistant prostate cancer. An androgen receptor inhibitor such as enzalutamide can inhibit the transcription of cancer cells by inhibiting the binding of dihydrotestosterone and an androgen receptor to form a transcription factor; cepharanthine hydrochloride can synergistically enhance the inhibition effect of Cepharanthine hydrochloride on the growth of cancer cells. The combined drug of stephanine hydrochloride and androgen receptor inhibitor has good application prospect in the preparation field of anti-prostate cancer drugs.
Description
Technical Field
The invention belongs to the field of biological medicine, and in particular relates to application of a medicine combination containing stephanine hydrochloride in treating prostate cancer.
Background
Cepharanthine (CEP) is a double-knot-based isowulin alkaloid extracted from stephania tetrandra of the family Menispermaceae, and has been purified and named in 1934. Has the research on the effects of resisting tumor, malaria, inhibiting bacteria, regulating immune function and the like of stephanine. It is approved by the Ministry of health of Japan for the clinical treatment of leukopenia, alopecia areata and alopecia totalis caused by radiotherapy. The stephanine has been used as a medicament for increasing leucocyte in Japanese clinic for more than 60 years, and has no obvious toxic or side effect. The stephanine can regulate body immunity, act with cell membrane to keep cell membrane stable, relax blood vessel and enhance blood circulation under reasonable dosage. Cepharanthine can be applied to clinical treatment in the forms of powder, tablets and injection. In recent reports, stephanine can inhibit proliferation of novel coronavirus (SARS-CoV-2), and at the same time, more and more in vitro and in vivo studies show that stephanine can reverse cancer cell resistance to anticancer drugs, but the anticancer effect of stephanine alone is not obvious. Therefore, stephanine is often used as an auxiliary anticancer therapeutic.
Enzalutamide (Enzalutamide) is a phenylsulfhydrylanthraquinone derivative, which is a representative drug of a second-generation androgen receptor inhibitor and is an effective therapeutic drug for patients with castration-resistant prostate cancer. Compared with the first generation of anti-prostate cancer drugs, the androgen receptor inhibitors such as enzalutamide and the like have the advantages of better curative effect, higher safety, smaller side effect and the like. However, long-term use of the drug causes castration-resistant prostate cancer cells to develop resistance.
However, to date, there has been no study of the combination of stephanine hydrochloride and enzalutamide.
Disclosure of Invention
The present invention aims to solve at least one of the technical problems in the prior art described above. Therefore, the invention provides a drug combination which has good application prospect in treating castration-resistant prostate cancer.
The invention also provides application of the drug combination.
According to one aspect of the present invention, a pharmaceutical combination is presented comprising as active ingredients:
stephanine hydrochloride and androgen receptor inhibitors.
According to a preferred embodiment of the invention, there is at least the following advantageous effect: to date, the combination of stephanine hydrochloride and androgen receptor inhibitor, the combination dosage and the medicine proportion have not been reported yet. The scheme of the invention skillfully combines the two, and the combination of stephanine hydrochloride and an androgen receptor inhibitor can achieve the effect of remarkably treating castration resistant prostate cancer. An androgen receptor inhibitor such as enzalutamide can inhibit the transcription of cancer cells by inhibiting the binding of dihydrotestosterone and an androgen receptor to form a transcription factor; cepharanthine hydrochloride can synergistically enhance the inhibition effect of Cepharanthine hydrochloride on the growth of cancer cells. The invention uses stephanine hydrochloride to strengthen the sensitivity of castration resistant prostate cancer cells to androgen receptor inhibitors and reduce the drug resistance degree of castration resistant prostate cancer cells; the selected anticancer drug stephanine hydrochloride is a natural product approved for clinical use, has little or no side effect, and has simple and economic acquisition mode; the invention discovers that the combination of stephanine hydrochloride and the androgen receptor inhibitor has better cancer inhibiting effect than the single effect in vivo and in vitro, provides a more optimal scheme for the clinical treatment of castration resistant prostate cancer, and has wide sources of the two combined medicines, and is economical and effective.
In some embodiments of the invention, the androgen receptor inhibitor comprises enzalutamide. The invention discovers that the anticancer effect of the enzalutamide in vitro and in vivo is enhanced by using the stephanine hydrochloride for the first time, and the anticancer effect is verified on an in vivo mouse model, thereby providing a novel and efficient solution for clinically treating castration resistant prostate cancer. On the premise that the enzalutamide is proved to have good cancer inhibiting effect in vivo and in vitro as a typical representative drug of the androgen receptor inhibitor, the person skilled in the art can know that other androgen receptor inhibitors have good anticancer effect.
In some preferred embodiments of the invention, the molar ratio of stephanine hydrochloride to androgen receptor inhibitor is 1:1 to 25. The method comprises the following steps: 5. 1:10 or 1:20.
in some more preferred embodiments of the invention, the molar ratio of stephanine hydrochloride to androgen receptor inhibitor is 1:1 to 20.
In some more preferred embodiments of the invention, the molar ratio of stephanine hydrochloride to androgen receptor inhibitor is 1:5 to 10.
In some preferred embodiments of the invention, the concentration of stephanine hydrochloride is 1 to 1000 μmol/L when the pharmaceutical combination is administered. Such as 10. Mu. Mol/L, 20. Mu. Mol/L, 50. Mu. Mol/L, 100. Mu. Mol/L, 200. Mu. Mol/L, 500. Mu. Mol/L, etc.
In some preferred embodiments of the invention, the concentration of androgen receptor inhibitor is 1 to 1000 μmol/L when the pharmaceutical combination is administered. Such as 10. Mu. Mol/L, 20. Mu. Mol/L, 50. Mu. Mol/L, 100. Mu. Mol/L, 200. Mu. Mol/L, 500. Mu. Mol/L, etc.
In some preferred embodiments of the invention, the stephanine hydrochloride is dosed at 1-1000 mg/kg. Such as 10mg/kg, 20mg/kg, 40mg/kg, 50mg/kg, 100mg/kg, 200mg/kg, 500mg/kg, etc.
In some preferred embodiments of the invention, the androgen receptor inhibitor is administered in a dose of 1 to 1000mg/kg. Such as 10mg/kg, 20mg/kg, 40mg/kg, 50mg/kg, 100mg/kg, 200mg/kg, 500mg/kg, etc.
In some preferred embodiments of the invention, the pharmaceutical combination, when administered to an animal, has a stephanine hydrochloride to androgen receptor dosage ratio of 1 to 25:1. the method comprises the following steps: 4. 1: 10. 1:16 or 1:20.
in some preferred embodiments of the invention, the pharmaceutical combination, when administered to an animal, has a stephanine hydrochloride to androgen receptor dosage ratio of 1 to 4:1.
according to another aspect of the invention, the use of the above pharmaceutical combination for the preparation of a medicament for the treatment of prostate cancer is presented.
The use according to a preferred embodiment of the invention has at least the following advantages: the stephanine hydrochloride belongs to semisynthetic derivatives of alkaloids, and the stephanine monomer is used as oral medicine for treating leucopenia, alopecia areata and alopecia totalis clinically. The related results of the specific embodiment of the invention show that stephanine hydrochloride has the effect of resisting prostate cancer in vitro and in vivo, and can resist the drug resistance of cancer cells to drugs when being combined with androgen receptor inhibitors represented by enzalutamide. Therefore, the combined use of stephanine hydrochloride and androgen receptor inhibitor has good application prospect in the preparation field of anti-prostate cancer drugs.
In some preferred embodiments of the invention, the prostate cancer is castration-low resistant prostate cancer.
In some embodiments of the present invention, the preparation raw materials of the medicament for treating prostate cancer further comprise pharmaceutical excipients.
In some embodiments of the invention, the pharmaceutical excipients are selected from at least one of disintegrants, diluents, lubricants, binders, flavoring agents, suspending agents, surfactants or preservatives.
In some embodiments of the invention, the disintegrant is selected from at least one of corn starch, potato starch, crosslinked polyvinylpyrrolidone, sodium carboxymethyl starch, low substituted hydroxypropyl cellulose, crosslinked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, or alginic acid.
In some embodiments of the invention, the diluent is selected from at least one of lactose, sucrose, mannitol, corn starch, potato starch, calcium phosphate, calcium citrate, or crystalline cellulose.
In some embodiments of the invention, the lubricant is selected from at least one of gum acacia, magnesium stearate, calcium stearate, stearic acid, talc, or anhydrous gum acacia.
In some embodiments of the invention, the binder is selected from at least one of acacia, gelatin, dextrin, hydroxypropyl cellulose, methylcellulose, or polyvinylpyrrolidone.
In some embodiments of the invention, the flavoring agent is selected from at least one of aspartame, stevioside, sucrose, maltitol, or citric acid.
In some embodiments of the invention, the suspending agent is selected from at least one of acacia, gelatin, methylcellulose, sodium carboxymethylcellulose, hydroxymethyl cellulose, or aluminum stearate gel.
In some embodiments of the invention, the surfactant is selected from at least one of lecithin, sorbitan monooleate, or glycerol monostearate.
In some embodiments of the invention, the preservative is selected from at least one of methylparaben or propylparaben.
In some embodiments of the invention, the pharmaceutical dosage form is in the form of a solid, semi-solid or liquid.
In some embodiments of the invention, the pharmaceutical dosage form is an aqueous solution, a non-aqueous solution, a suspension or a paste.
In some embodiments of the invention, the pharmaceutical dosage form is a tablet, capsule, granule, pill, oral liquid, emulsion, dry suspension, dry extract or injection.
In some embodiments of the invention, the pharmaceutical dosage form is a soft capsule.
Drawings
The invention is further described with reference to the accompanying drawings and examples, in which:
FIG. 1 shows that two active ingredients in the pharmaceutical combination of the embodiment of the invention are shown in 1: curve fitting of concentration-cell viability relationship at 5;
fig. 2 shows that two active ingredients in the pharmaceutical combination according to the embodiment of the invention are shown in 1: curve fitting of concentration-cell viability relationship at 10;
fig. 3 shows two active ingredients in the pharmaceutical combination according to the embodiment of the invention, wherein 1: curve fitting of concentration-cell viability relationship at 20;
FIG. 4 is a graph showing a curve fit of the concentration of the active ingredient of comparative example 1 to the cell viability;
FIG. 5 is a graph showing a curve fit of the concentration of the active ingredient of comparative example 2 to the cell viability;
fig. 6 shows the pharmaceutical combination of the embodiment of the invention, wherein two active ingredients are shown in 1: a joint index analysis chart at time 5;
FIG. 7 shows two active ingredients in the pharmaceutical combination according to the embodiment of the invention in 1: joint index analysis graph at 10;
FIG. 8 shows two active ingredients in the pharmaceutical combination according to the embodiment of the invention in 1: a joint index analysis graph at 20;
FIG. 9 is a graph showing the results of in vivo tumor growth inhibition in mice of pharmaceutical compositions of examples and comparative examples 1-2 of the present invention (p <0.001 is shown in the figure);
FIG. 10 is a photograph of prostate cancer cell mice transplanted tumor (corresponding to the same horizontal row in the figure, transplanted tumor of three mice in the same group) 12 days after application of the pharmaceutical compositions of the present invention and comparative examples 1 to 2.
Detailed Description
The conception and the technical effects produced by the present invention will be clearly and completely described in conjunction with the embodiments below to fully understand the objects, features and effects of the present invention. It is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments, and that other embodiments obtained by those skilled in the art without inventive effort are within the scope of the present invention based on the embodiments of the present invention. The test methods used in the examples are conventional methods unless otherwise specified; the materials, reagents and the like used, unless otherwise specified, are those commercially available.
In the description of the present invention, the descriptions of the terms "one embodiment," "some embodiments," "illustrative embodiments," "examples," "specific examples," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms do not necessarily refer to the same embodiments or examples. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.
Examples
The embodiment prepares a drug combination and application thereof in preparing a drug for treating prostate cancer, and the active ingredients of the drug combination consist of enzalutamide and stephanine hydrochloride. The specific process is as follows: the enzalutamide is weighed by an electronic balance, added into dimethyl sulfoxide (DMSO) for dissolution to prepare a mother solution with the concentration of 100mM, and then diluted into different concentrations by DMSO. The stephanine hydrochloride powder is weighed by an electronic balance, added into DMSO for dissolution to prepare a mother solution with the concentration of 100mM, and then diluted into different concentrations by DMSO.
The drug combinations described above were applied to prostate cancer 22RV1 cells to verify their in vitro inhibition of prostate cancer. The specific process is as follows:
prostate cancer 22RV1 cells (commercially available) were digested with pancreatin, the cells were inoculated into 96-well plates at 4000 cells/well, after overnight adherence was performed, the culture solution was removed, and the cells were assayed for viability by the tetramethylazofamid blue (MTT) method at different concentrations of stephanine (m=1 to 1000 μm) and different concentrations of enzalutamide (n=1 to 1000 μm) at molar ratios of 1:5,1:10,1:20, respectively (see table 1 for details, the final concentrations of each of the two drugs in the drug combinations at different mixing ratios listed in table 1), 100 μl of the mixed solution was added to the 96-well plates, and after incubation for 24 hours. After 24h incubation, 10. Mu.L MTT was added, incubated at 37℃for 4h, the MTT-containing broth was aspirated, 100. Mu.L MSO was added, the reaction was performed on a shaker at room temperature for 10min, absorbance was measured at 570nm, and then a fitted curve of drug concentration versus cell viability was drawn with GraphPad Prism 8.
TABLE 1
Comparative example 1
The comparative example provides the application of enzalutamide in preparing medicaments for treating the prostate cancer, which comprises the following specific processes: the enzalutamide is weighed by an electronic balance, added into DMSO for dissolution to prepare a mother solution with the concentration of 100mM, and then diluted into different concentrations by DMSO.
Enzalutamide was applied to prostate cancer 22RV1 cells to verify its inhibitory effect on prostate cancer in vitro.
The specific process is as follows:
toxicity of enzalutamide to prostate cancer 22RV1 cells for 24h was detected by using a method of tetramethyl azoazole blue (MTT), and IC of enzalutamide to prostate cancer cells was calculated 50 Values. The specific method comprises the following steps: prostate cancer 22RV1 cells are inoculated into a 96-well plate after being digested by pancreatin, 4000 cells are inoculated into each well, after being subjected to overnight culture for adherence, 100 mu L of 0-400 mu M enzalutamide is added into the 96-well plate, 10 mu L of MTT is added after 24 hours of culture, culture solution containing the MTT is sucked after 4 hours of incubation at 37 ℃, 100 mu L of DMSO is added, reaction is carried out on a shaker for 10 minutes at room temperature, the absorbance value is measured at 570nm, and then a fitted curve of drug concentration corresponding to the cell survival rate is drawn by using GraphPad Prism 8.
Comparative example 2
The comparative example provides the application of stephanine hydrochloride in preparing the medicine for treating the prostate cancer, which comprises the following specific processes: the stephanine hydrochloride powder is weighed by an electronic balance, added into DMSO for dissolution to prepare a mother solution with the concentration of 100mM, and then diluted into different concentrations by DMSO.
Stephanine hydrochloride was applied to prostate cancer 22RV1 cells to verify their inhibitory effect on prostate cancer in vitro. The specific process is as follows:
toxicity of stephanine hydrochloride to prostate cancer 22RV1 cells for 24h is detected by using a method of tetramethyl azosin blue (MTT), and IC of stephanine hydrochloride to prostate cancer cells is calculated 50 Values. The specific method comprises the following steps: prostate cancer 22RV1 cells are digested by pancreatin and inoculated into a 96-well plate, 4000 cells are inoculated into each well, after the cells are cultured overnight and are adhered, 100 mu L of 0-40 mu M stephanine hydrochloride is added into the 96-well plate, 10 mu L of MTT is added after the cells are cultured for 24 hours, the culture solution containing the MTT is sucked after incubation for 4 hours at 37 ℃, 100 mu L of DMSO is added, the reaction is carried out on a shaker at room temperature for 10 minutes, the absorbance value is measured at 570nm, and then a fitted curve of the drug concentration corresponding to the cell survival rate is drawn by using GraphPad Prism 8.
The fitted curves of drug concentration and cell viability plotted in examples and comparative examples 1-2 are shown in FIGS. 1-5. As can be seen from fig. 1 to 3, the results of fig. 4 and 5 show that stephanine hydrochloride and enzalutamide have a concentration dependence on toxicity of prostate cancer 22RV1 cells.
The combination index of the two active ingredients in the drug combinations of the examples was calculated and analyzed by CompuSyn software at different ratios, and the results are shown in FIGS. 6 to 8. As can be seen from fig. 6 to 8, the fitted curve drug combination index (CI value) of the drug concentration corresponding to the cell viability in a certain interval is less than 1, which indicates that the combination of stephanine and enzalutamide has a synergistic anti-tumor effect, and the ratio of the stephanine and enzalutamide is 1: the CI can reach below 0.4 under the molar ratio of 10, which shows that the two have strong synergistic effect.
Further, the drug combinations of the above examples or the drug monomers of comparative examples 1 to 2 were also applied to animal model mice to verify their inhibitory effect on prostate cancer in vivo. The specific process is as follows:
in nude mice tumor formation experiments, male BALB/c nude mice (4-6 weeks old) were purchased from beijing velutinin inc, china and placed in a pathogen free (SPF) environment. Prostate cancer 22RV1 cells (5X 10) suspended in 200. Mu.L matrigel/PBS (7.8 mg/mL) 6 ) Subcutaneous injection into the groin of mice was performed to construct a model of human prostate cancer nude mice transplantation tumor. When the tumor volume in the mouse grows to 100mm 3 The time period was randomly divided into 4 groups (5 control groups and 3 other groups). Each set of treatment protocol: (1) control group, saline 200 μl, i.p., qd; (2) single enzalutamide group, 10mg/kg (in 200 μl soybean oil), i.g., qd; (3) the single stephanine hydrochloride group, 40mg/kg (dissolved in 200 μl physiological saline), i.p., qd; (4) combination group: 10mg/kg of enzalutamide (dissolved in 200. Mu.L of soybean oil), i.g. + 40mg/kg of stephanine hydrochloride (dissolved in 200. Mu.L of physiological saline), i.p., qd. Mice were measured for body weight and tumor size every other day. Mice were sacrificed by cervical dislocation at day 12, transplanted tumors and livers were collected, weighed and fixed with 4% paraformaldehyde for immunohistochemical analysis.
The results are shown in FIGS. 9 to 10. As can be seen from the figure, the drug combination regimen significantly improved tumor inhibition effect after day 6 over the drug monomer group.
From the results, the single use of stephanine hydrochloride has a certain effect on the growth of castration-resistant prostate cancer cells, and the combination of the androgen receptor inhibitor and stephanine hydrochloride commonly used in clinical treatment is designed and used, so that the combination of medicines is proved to synergistically inhibit the growth of castration-resistant prostate cancer cells in vitro; the enzalutamide serving as an androgen receptor inhibitor and stephanine hydrochloride combined drug has the effect of inhibiting castration resistant prostate cancer in vivo and in vitro, and the combined use of the two drugs has better tumor inhibition effect in vivo and in vitro, and can obviously inhibit the growth of cancer cells; analysis of the combination therapy cancer combination index of both using CompuSyn software, preferably the ratio of stephanine hydrochloride to enzalutamide 1:10, inhibits cancer cells in vitro; the drug addition amount is calculated according to the combination index of in vitro experiments, the mice are used together daily, and the combination of stephanine hydrochloride and enzalutamide is found to have better treatment effect than the single drug according to the abnormal conditions of the tumor size, the body weight and various organs of the mice, and has no side effect on important tissues and organs. After the in vitro verification that the combination of the stephanine hydrochloride and the enzalutamide has the synergistic cancer inhibiting effect, the combination is further verified in the nude mice, and meanwhile, the combination has no side effect on organs of animal models, so that the medicine combination has good application prospect in preparing medicines for treating the prostate cancer.
The embodiments of the present invention have been described in detail with reference to the accompanying drawings, but the present invention is not limited to the above embodiments, and various changes can be made within the knowledge of one of ordinary skill in the art without departing from the spirit of the present invention. Furthermore, embodiments of the invention and features of the embodiments may be combined with each other without conflict.
Claims (10)
1. A pharmaceutical combination, characterized in that: comprises the following substances as active ingredients: stephanine hydrochloride and androgen receptor inhibitors.
2. A pharmaceutical combination according to claim 1, wherein: the androgen receptor inhibitor includes enzalutamide.
3. A pharmaceutical combination according to claim 1, wherein: the molar ratio of stephanine hydrochloride to androgen receptor inhibitor is 1:1 to 25.
4. A pharmaceutical combination according to claim 1, wherein: the molar ratio of stephanine hydrochloride to androgen receptor inhibitor is 1:1 to 20.
5. A pharmaceutical combination according to claim 1, wherein: the molar ratio of stephanine hydrochloride to androgen receptor inhibitor is 1:5 to 10.
6. A pharmaceutical combination according to claim 1, wherein: when the drug combination is used, the concentration of the stephanine hydrochloride is 1-1000 mu mol/L; preferably, the concentration of the androgen receptor inhibitor is 1-1000 mu mol/L when the drug combination is administered.
7. A pharmaceutical combination according to claim 1, wherein: the dosage of the stephanine hydrochloride is 1-1000 mg/kg; preferably, the dosage of the androgen receptor inhibitor is 1-1000 mg/kg.
8. A pharmaceutical combination according to claim 1, wherein: when the drug combination is used for animals, the dosage ratio of the stephanine hydrochloride to the androgen receptor is 1-25: 1, a step of; preferably, when the drug combination is used for animals, the dosage ratio of stephanine hydrochloride to androgen receptor is 1-4: 1.
9. use of a pharmaceutical combination according to any one of claims 1 to 8 for the preparation of a medicament for the treatment of prostate cancer.
10. The use according to claim 9, characterized in that: the prostate cancer is castration-low resistant prostate cancer.
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