CN106491603B - Medicinal composition containing capsaicin and sorafenib and application thereof - Google Patents
Medicinal composition containing capsaicin and sorafenib and application thereof Download PDFInfo
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- CN106491603B CN106491603B CN201611112946.2A CN201611112946A CN106491603B CN 106491603 B CN106491603 B CN 106491603B CN 201611112946 A CN201611112946 A CN 201611112946A CN 106491603 B CN106491603 B CN 106491603B
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
Abstract
The invention belongs to the field of antitumor drugs, and particularly relates to a pharmaceutical composition containing capsaicin and sorafenib. The molar ratio of capsaicin to sorafenib in the pharmaceutical composition is 5: 1-10: 1. Sorafenib is the only chemotherapy drug for the liver cancer system in the global scope at present, but the curative effect of sorafenib needs to be further improved. The pharmaceutical composition can obviously inhibit the proliferation of liver cancer cells and induce the apoptosis of tumor cells, and the combined application of the two shows good synergistic effect.
Description
Technical Field
The invention relates to the field of antitumor drugs, and in particular relates to a pharmaceutical composition containing capsaicin and sorafenib and application thereof.
Background
Primary liver cancer is one of common malignant tumors worldwide, the morbidity and the mortality of the primary liver cancer are on an increasing trend year by year, and the health of human beings is seriously threatened. In China, the incidence and mortality of liver cancer are particularly severe due to the existence of serious carcinogenic risk factors such as hepatitis B virus infection. According to the statistical report issued by the world health organization 2014, the number of new cases of the Chinese liver cancer in 2012 exceeds 40 thousands, and accounts for about 55% of the total number of new cases in the world. Liver cancer is occult, most patients are in the middle and late stages when the diagnosis is confirmed for the first time, and the best time for surgical treatment is lost. Local therapies such as rf ablation and hepatic artery chemoembolization are also limited in dealing with micrometastasis. Therefore, systemic chemotherapy is a clinically urgent therapeutic approach.
The targeted drug sorafenib (sorafinib) is a chemotherapy drug approved to be applied to clinical liver cancer and kidney cancer systems in a plurality of countries such as the United states, European Union and China in recent years. Sorafenib exerts an anti-tumor effect through a dual mechanism: on one hand, the tumor growth is directly inhibited by inhibiting a RAF/MEK/ERK signaling pathway of tumor cells; on the other hand, it can indirectly inhibit the growth of tumor cells by inhibiting Vascular Endothelial Growth Factor Receptor (VEGFR) and Platelet Derived Growth Factor Receptor (PDGFR) to block the formation of tumor new blood vessels. Sorafenib is a milestone discovery in the liver cancer molecular targeted drug therapy, and plays an irreplaceable therapeutic role in the late-stage liver cancer comprehensive treatment scheme. Nevertheless, the clinical efficacy of sorafenib has not been fully satisfactory. Clinical practice shows that liver cancer has different degrees of congenital drug resistance to sorafenib, and only 43% of patients treated by sorafenib can be controlled in a short term. Therefore, the exploration of the medicine capable of enhancing the curative effect of sorafenib, in particular to the natural medicine-food homologous substance with small toxic and side effect on human body, has very important significance.
CN103933039A discloses a composition of sorafenib and a natural medicine silibinin, which have synergistic effect in inhibiting the growth and proliferation of liver cancer cells. CN102836160A discloses a composition of sorafenib and a chemically synthesized small molecular substance ABT-263, and the combined use of the sorafenib and the ABT-263 has synergistic and synergistic effects on the anti-tumor effect.
The pepper is a kind of vegetable and seasoning widely eaten by people, and the pungent taste is derived from the capsaicinoids contained in the pepper, including capsaicin (capsaicin), dihydrocapsaicin (dihydrocasaicin), nordihydrocapsaicin (norbihydrocapsaiin) and the like. Capsaicin is the highest component of the capsaicinoid, and accounts for about 69% of the total amount. Capsaicin has many pharmacological activities and can be used for analgesia, anti-inflammation and the like. Recent researches show that capsaicin also has certain antitumor activity and has the effects of inhibiting proliferation and inducing apoptosis on malignant tumor cells such as liver cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, bladder cancer and the like. The antitumor effect of capsaicin is related to the following factors: increase cell membrane permeability, inhibit mitochondrial respiration; up-regulating the expression of an anti-cancer gene p53 and inhibiting a cell signal transduction pathway JNK; increasing the content of active oxygen in cells.
CN104447777A discloses a capsaicin-camptothecin anticancer drug conjugate, which can directly release capsaicin and camptothecin drugs in vivo in a hydrolysis manner, and the two have synergistic antitumor effects. CN104983900A discloses that the combination of capsicum extract and proanthocyanidin can prevent nausea and emesis caused by cancer chemotherapy, and has the effect of auxiliary tumor inhibition.
At present, no report on the treatment of malignant tumor by using capsaicin and sorafenib in combination is available.
Disclosure of Invention
The purpose of the invention is as follows: in order to solve the problems in the prior art, the invention provides a medicinal composition containing capsaicin and sorafenib and application thereof, and the anti-tumor effect is improved.
The technical scheme is as follows: in order to achieve the technical purpose, the invention provides a pharmaceutical composition containing capsaicin and sorafenib, wherein the molar ratio of the capsaicin to the sorafenib in the pharmaceutical composition is 5: 1-10: 1.
Preferably, in the pharmaceutical composition containing capsaicin and sorafenib, the molar ratio of the capsaicin to the sorafenib is 10: 1.
Wherein, the pharmaceutical composition containing capsaicin and sorafenib also comprises a pharmaceutically acceptable carrier, and the pharmaceutically acceptable carrier can be a medicinal carrier well known by the technical personnel in the field.
The invention also provides the application of the pharmaceutical composition in preparing a medicament for treating malignant tumor.
Wherein the malignant tumor is any one of primary liver cancer and kidney cancer.
The pharmaceutical composition of the present invention can be administered in various oral dosage forms commonly used in pharmacy. The various oral dosage forms commonly used in the pharmacy can be tablets, capsules, granules, oral liquid and the like.
In addition, the single active drug or the pharmaceutical composition in the pharmaceutical composition can be prepared into sustained-release preparations, such as sustained-release tablets, micro-pills or controlled-release tablets, according to the conventional method.
Pharmacological tests show that the pharmaceutical composition containing capsaicin and sorafenib has the function of synergistically treating malignant tumors such as primary liver cancer and the like, and the malignant tumors are preferably primary liver cancer and kidney cancer.
Has the advantages that: compared with the prior art, the medicinal composition containing capsaicin and sorafenib has an anti-tumor effect remarkably stronger than that of a single medicament, and the combined use of the capsaicin and the sorafenib can enable the medicament effects to generate a synergistic effect. Particularly, when the molar ratio of capsaicin to sorafenib is 10:1, the synergistic effect of the capsaicin and the sorafenib is best.
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FIG. 1 inhibition of tumor cell proliferation by sorafenib in combination with capsaicin
FIG. 2 Effect of Sorafenib in combination with capsaicin on tumor cell morphology
FIG. 3 Effect of Sorafenib in combination with capsaicin on Caspase 3/7 Activity of tumor cells
Detailed Description
Tumor cell lines used in the following examples were derived from: the liver cancer cell PLC/PRF/5 and the kidney cancer cell OS-RC-2 are from the cell bank of the China academy of sciences type culture Collection.
Drugs and reagents: sorafenib is available from seleck Chemicals, usa; capsaicin is available from Tocris corporation, uk. Both drugs were dissolved in dimethyl sulfoxide (DMSO), stored at-80 ℃ and diluted to working concentration at the time of the experiment (DMSO concentration < 0.5%). MTT (3- (4, 5-dimethylthiozol-2-yl) -2,5-diphenyltetrazolium bromide), Hoechst33258, Propidium Iodide (PI) and Caspase 3/7 detection reagents were purchased from ThermoFisher, USA.
Example 1 half Inhibitory Concentration (IC) of Sorafenib and capsaicin on tumor cells50) The measurement of (1).
In the embodiment, the MTT method is adopted to determine the inhibition effect of capsaicin and sorafenib on liver cancer cell PLC/PRF/5 and kidney cancer cell OS-RC-2. The cells were cultured at 5X 104The cells were inoculated in a 96-well plate at a concentration of 100. mu.L/well and cultured overnight with the drug added after the cells were adherent. Sorafenib was set to 5 drug concentrations, 0.3, 1, 3, 10, 30 μ M respectively; capsaicin is provided with 5 drug concentrationsDegrees are 10, 30, 100, 300, 1000. mu.M, respectively. After the cells were incubated with the drug solution in the incubator for 72 hours, 10. mu.L of MTT solution (5mg/mL) was added to each well, incubated at 37 ℃ for 4 hours, the medium was discarded, 150. mu.L of DMSO was added to each well, and the wells were left at 37 ℃ for 1 hour, and then the absorbance (OD) of each well was measured at 490nm using a microplate reader to calculate the inhibition rate of the drug on the cells. The cellular inhibition rate is calculated by the formula: the inhibition (%) was (control OD value-test OD value)/(control OD value-blank OD value) × 100%.
The results show that both sorafenib and capsaicin can inhibit the proliferation of tumor cells in a dose-dependent manner. The half inhibitory concentrations of sorafenib on PLC/PRF/5 and OS-RC-2 cells were 7.6 and 17.0. mu.M, respectively. The half inhibitory concentrations of capsaicin for PLC/PRF/5 and OS-RC-2 cell proliferation were 137.0 and 169.8. mu.M, respectively.
Example 2 inhibition of tumor cell proliferation by sorafenib in combination with capsaicin.
The PLC/PRF/5 and OS-RC-2 cells in the logarithmic growth phase were cultured at 5X 104The cells were inoculated in a 96-well plate at a concentration of 100. mu.L/well and cultured overnight with the drug added after the cells were adherent. The experimental groups were as follows: a negative control group, a capsaicin group, a sorafenib group, a capsaicin and sorafenib combined administration group. The capsaicin component is administered with 10, 50, and 100 μ M capsaicin respectively; the sorafenib group was given 10 μ M sorafenib; capsaicin and sorafenib are added into the combined drug group according to the proportion of 1:1, 5:1 and 10:1 (the combined drug group 1: capsaicin 10 muM + sorafenib 10 muM; the combined drug group 2: capsaicin 50 muM + sorafenib 10 muM; and the combined drug group 3: capsaicin 100 muM + sorafenib 10 muM). After the cells and the drug solution are incubated in an incubator for 72 hours, 10. mu.L of MTT solution (5mg/mL) is added to each well, the cells are incubated at 37 ℃ for 4 hours, the medium is discarded, 150. mu.L of DMSO is added to each well, the cells are left at 37 ℃ for 1 hour, and then the absorbance of each well is measured at 490nm by using a microplate reader, and the inhibition rate of the drug on the proliferation of tumor cells is calculated. The type of interaction (antagonistic, additive or synergistic) of sorafenib and capsaicin was determined using the Chou-Talalay combined index method. The CompuSyn software was used to calculate the drug Combination Index (CI), which was judged to be additive when the CI value was in the range of 0.90-1.10,synergy is judged when the CI value is less than 0.90 and antagonism is judged when the CI value is greater than 1.1.
The experimental result is shown in figure 1, when the concentration of capsaicin is 10 mu M, the inhibition effect of sorafenib on PLC/PRF/5 and OS-RC-2 cells cannot be obviously enhanced (combination drug 1, p is greater than 0.05), but when the concentration is 50 mu M and 100 mu M, the anti-proliferation effect of sorafenib can be obviously enhanced (combination drug 2 and combination drug 3, p is less than 0.01), and the fact that when the molar ratio of capsaicin to sorafenib is 5: 1-10: 1 is suggested, the curative effect of the pharmaceutical composition can be obviously better than that of a single drug. The combined effect index CI for both drugs was further calculated as follows: in PLC/PRF/5 cells, when the molar ratio of capsaicin to sorafenib is 5:1 and 10:1, the CI values are 1.09 and 0.55 respectively, which indicates that the former is additive effect and the latter is synergistic effect; the CI values were 0.43 and 0.32 at molar ratios of capsaicin to sorafenib of 5:1 and 10:1 in OS-RC-2 cells, respectively, suggesting that the drug interactions were synergistic at both ratios, but the synergistic effect of the latter was more pronounced. The above results indicate that additive or synergistic antitumor effect can be obtained when the molar ratio of capsaicin to sorafenib is 5:1, and synergistic antitumor effect is shown for both cells when the molar ratio is 10: 1.
Example 3 effect of capsaicin in combination with sorafenib on tumor cell morphology.
The PLC/PRF/5 and OS-RC-2 cells in the logarithmic growth phase were cultured at 1X 105The cells were inoculated in a 96-well plate at a concentration of 100. mu.L/well and cultured overnight with the drug added after the cells were adherent. The experimental groups were as follows: a negative control group, a capsaicin group, a sorafenib group, a capsaicin and sorafenib combined administration group. Capsaicin group was given 100 μ M capsaicin; the sorafenib group was given 10 μ M sorafenib; the combination group was given 100 μ M capsaicin and 10 μ M sorafenib simultaneously. After 24 hours of incubation of the cells with the drug in the incubator, the morphology of the cells was observed with an inverted phase contrast microscope.
The photograph of the liver cancer PLC/PRF/5 cells after being treated by different drugs is shown in figure 2A: the negative control group cells are naturally spread at the bottom of the hole, the appearance is soft and full, and the shape is normal; in the sorafenib treatment group, cells are shriveled, part of the cells are detached from the wall, black granular substances in cytoplasm are increased, and vacuoles appear, so that the cells are prompted to show signs of apoptosis under the action of the medicine; in the capsaicin treatment group, granular substances in cells are increased, and the cell membrane of part of the cells is shrunk; in the combined treatment group of capsaicin and sorafenib, a large number of cells are detached from the wall and become round, and partial cells are broken, so that apoptosis of the cells is prompted. The change of the shape of the kidney cancer OS-RC-2 cell after the drug treatment is similar to that of a PLC/PRF/5 cell. The experimental result shows that the capsaicin and sorafenib have the greatest influence on the appearance and the shape of the tumor cells and prompt that the cells are likely to undergo apoptosis under the treatment of the medicine.
Example 4 sorafenib in combination with capsaicin induced apoptosis in tumor cells.
The influence of sorafenib, capsaicin and the combination of sorafenib and capsaicin on PLC/PRF/5 cell apoptosis is detected by adopting a Hoechst33258 and PI double staining method. PLC/PRF/5 cells at 5X 104The concentration of the suspension is inoculated in a 24-well culture plate, each well is 2mL, and the suspension is cultured overnight, and the medicine is added after the cells are attached to the wall. The dosing regimen was designed as follows: capsaicin group was given 100 μ M capsaicin; the sorafenib group was given 10 μ M sorafenib; the combination group was given 100 μ M capsaicin and 10 μ M sorafenib simultaneously. Incubating the cells and the medicine in an incubator for 24 hours, collecting the cells, staining by Hoechst33258 and PI respectively, observing by using an immunofluorescence microscope, randomly photographing in 5 different areas, counting the number of the cells undergoing apoptosis and the total number of the cells, and calculating the apoptosis rate.
The results of Hoechst33258 and PI double-staining experiments show that the apoptosis rate of negative control group cells is 0.41%, the apoptosis rate of capsaicin group cells is 4.22%, the apoptosis rate of sorafenib group cells is 9.76%, and the apoptosis rate of capsaicin and sorafenib combined group cells is 30.58%. The apoptosis rate of the combined medicine group is obviously higher than that of the sorafenib group and the capsaicin group (p is less than 0.05).
Example 5 Effect of capsaicin in combination with Sorafenib on the Activity of the apoptosis-related protein Caspase 3/7
Caspase cascade activation can directly lead to apoptosis. In the embodiment, a fluorescence microscope is adopted to detect the influence of capsaicin and sorafenib on the activity of the Caspase 3/7 of the liver cancer PLC/PRF/5 cells. Will PLCPerPRF/5 cells at 2.5X 105The cells were inoculated in a 24-well plate at a concentration of 400. mu.L/well and cultured overnight with the drug added after the cells were adherent. The dosing regimen was designed as follows: the concentration of the capsaicin group medicine is 100 mu M; the concentration of the sorafenib drug is 10 mu M; capsaicin and sorafenib (at the same concentrations) were added to the combination. Incubating the cells and the medicament in an incubator for 24 hours, removing the culture medium, adding a Caspase 3/7 detection reagent CellEventTMCaspase-3/7Green Detection Reagent, incubated at 37 ℃ for 20 minutes and observed by fluorescence microscopy. Caspase 3/7 activated cells appeared green fluorescent, and 5 fields per well were randomly selected, counted and averaged.
The result is shown in fig. 3, the number of cells showing green fluorescence in the combined drug group is obviously more than that of the sorafenib or capsaicin single drug group (p is less than 0.05), and the combined drug is prompted to more effectively activate Caspase 3/7 in PLC/PRF/5 cells, so that apoptosis of the cells is induced.
Claims (1)
1. A pharmaceutical composition containing capsaicin and sorafenib, which is characterized in that: the molar ratio of capsaicin to sorafenib in the pharmaceutical composition is 10:1, the two drugs are dissolved by dimethyl sulfoxide and stored at-80 ℃, the concentration of the dimethyl sulfoxide is less than 0.5%, the pharmaceutical composition has an inhibition effect on liver cancer cells PLC/PRF/5 and kidney cancer cells OS-RC-2, and shows a synergistic antitumor effect on the two cells.
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