CN112190573A - Combined medicine for treating liver cancer - Google Patents
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Abstract
The invention provides a combined medicament for treating liver cancer, which comprises a serotonin reuptake inhibitor and an antitumor medicament which are prepared from unit preparations with the same or different specifications and are used for simultaneous or separate administration, and a pharmaceutically acceptable carrier. The serotonin reuptake inhibitor and the antitumor drug are used in combination, so that the serotonin reuptake inhibitor and the antitumor drug have synergistic effect and good clinical application prospect.
Description
Technical Field
The invention relates to the field of anti-cancer drugs, in particular to a combined drug for treating hepatocellular carcinoma.
Background
Hepatocellular carcinoma is the most common pathological subtype of primary liver cancer, the fifth largest primary malignancy worldwide, and the second largest cause of cancer-related death. Although there are several liver cancer treatment methods in clinical practice, the prognosis of hepatocellular carcinoma is very poor because the clinical manifestations of hepatocellular carcinoma are atypical in early stage, and most hepatocellular carcinoma patients are diagnosed in late stage and miss the best treatment opportunity. Sorafenib, a first-line treatment drug for liver cancer approved by the U.S. Food and Drug Administration (FDA), significantly improves median survival in patients with hepatocellular carcinoma, but the clinical benefit of sorafenib in the treatment of hepatocellular carcinoma is limited due to primary or secondary drug resistance.
mTOR pathway activation is seen in a variety of tumors, is involved in the development of tumors, and can lead to sorafenib resistance. Clinical trials have not had sufficient evidence for the antitumor efficacy of several commonly used mTOR pathway inhibitors, and thus no mTOR inhibitor is currently approved for routine clinical use against tumors.
Clinically, patients with tumors are often associated with mood disorders of varying degrees. Serotonin inhibitors, selective 5-HT reuptake inhibitors (SSRIs), are the most widely used clinically as antidepressants, and are commonly used to treat the depressed mood of patients with tumors. Sertraline and fluoxetine are the most common types of such antidepressants. At present, clinical studies show that the application of the serotonin reuptake inhibitor can reduce the incidence rate of various tumors including liver cancer, and numerous preclinical studies also show that the serotonin reuptake inhibitor can inhibit an mTOR pathway.
However, in the treatment of hepatocellular carcinoma, the action relationship of the serotonin reuptake inhibitor on an mTOR pathway is not clear, so that the specific proportional dose and the exact effect of the combination of the serotonin reuptake inhibitor and sorafenib in the treatment of hepatocellular carcinoma are not reported yet.
In order to solve the problem of drug resistance of sorafenib, the combined drug of sorafenib and a 5-HT reuptake inhibitor which is commonly used in clinic is explored, so that the drug has very important significance for treating liver cancer patients, and has good clinical application prospect.
Disclosure of Invention
The invention aims to provide a combined medicament for treating liver cancer.
The invention provides a combined medicament for treating liver cancer, which is characterized by comprising a serotonin reuptake inhibitor and an antitumor medicament which are prepared from unit preparations with the same or different specifications and are used for simultaneous or separate administration, and a pharmaceutically acceptable carrier;
the serotonin reuptake inhibitor is sertraline or fluoxetine, and/or the antitumor drug is sorafenib.
Further, the above combination is a combination for treating hepatocellular carcinoma.
Further, the concentrations of the sertraline and the antitumor drug are 2.5 μ M and 5 μ M, respectively; or the mass ratio of the sertraline to the anti-tumor medicine is 1: 1.
Furthermore, the concentration ratio of the fluoxetine to the antitumor drug is (3.75-5 mu M) to 5 mu M, and the molar ratio is (0.75-1) to 1.
Furthermore, the concentration ratio of the fluoxetine to the antitumor drug is 3.75 muM to 5 muM or 5 muM to 5 muM, and the molar ratio is 0.75:1 or 1: 1.
The invention also provides application of the combined medicament in preparing a medicament for treating liver cancer, and preferably the medicament for treating liver cancer is a medicament for treating hepatocellular carcinoma.
The invention also provides application of the serotonin reuptake inhibitor and the anti-tumor drug in preparing the combined drug for treating liver cancer, wherein the serotonin reuptake inhibitor is sertraline or fluoxetine, and/or the anti-tumor drug is sorafenib; preferably, the combination drug for treating liver cancer is a combination drug for treating hepatocellular carcinoma.
Further, the concentrations of the sertraline and the antitumor drug are 2.5 μ M and 5 μ M, respectively; or the mass ratio of the sertraline to the anti-tumor medicine is 1: 1.
Furthermore, the concentration ratio of the fluoxetine to the antitumor drug is (3.75-5 mu M) to 5 mu M, and the molar ratio is (0.75-1) to 1.
Furthermore, the concentration ratio of the fluoxetine to the antitumor drug is 3.75 muM to 5 muM or 5 muM to 5 muM, and the molar ratio is 0.75:1 or 1: 1.
Experimental results show that the serotonin reuptake inhibitor Sertraline or Fluoxetine used in the invention has a synergistic effect when combined with sorafenib, can effectively inhibit the growth of hepatocellular carcinoma cell lines in vivo or in vitro, and has an anticancer effect obviously superior to that of the serotonin reuptake inhibitor Sertraline (Sertraline) and Fluoxetine (Fluoxetine) or sorafenib used alone. On the basis, the medicinal composition or preparation of SSRIs and sorafenib can be further prepared in a pharmaceutically acceptable mode such as pharmaceutical excipients. Meanwhile, sertraline, fluoxetine and sorafenib which are used in combination are all clinical common drugs, are safe and effective, and have good clinical application prospects.
The serotonin reuptake inhibitor referred to in the invention is also named as 5-HT reuptake inhibitor, selective 5-HT reuptake inhibitor, 5-serotonin reuptake inhibitor and SSRIs.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Drawings
Figure 1 sertraline or fluoxetine enhanced the cytotoxic effects of sorafenib: (A) detecting cell proliferation by MTT after sorafenib action; (B-C) MTT detecting cell proliferation after combining sertraline or fluoxetine with sorafenib, respectively; (D-E) cloning experiments after combining sertraline or fluoxetine with sorafenib respectively; (F) a combination index;
FIG. 2(A-D) Western immunoblots of HepG2, Huh7.5.1 cells affected by sertraline in combination with sorafenib or fluoxetine in combination with sorafenib.
Figure 3 sertraline or fluoxetine enhanced the anti-hepatocellular carcinoma effect of sorafenib in the primary liver cancer model: (A) in the primary liver cancer model, the tumor volume is inhibited by the independent application of sertraline or fluoxetine, and the effect of sorafenib and the effect of independent application of sertraline or fluoxetine on resisting liver cancer can be enhanced after the sertraline or fluoxetine is respectively combined with sorafenib; (B) in vivo tumor volume inhibition statistical graphs of sertraline or fluoxetine applied alone or separately in combination with sorafenib; (C) statistical figures for in vivo tumor number inhibition using sertraline or fluoxetine alone or in combination with sorafenib, respectively.
Description of the drawings: in the figure, sertraline represents sertraline, fluoxetine represents fluoxetine, sorafenib represents sorafenib, DEN represents dimethylnitrosamine, CCL4 represents carbon tetrachloride, DMSO represents dimethyl sulfoxide, and indicates a significant difference (p < 0.05); indicates very significant differences (p < 0.01); indicates a very significant difference (p < 0.001).
Detailed Description
Experiment raw materials: sertraline, fluoxetine and sorafenib were purchased from shanghai ceramic biochemistry ltd. DMEM medium (Gibio, USA), fetal bovine serum (Gibio, USA). MTT kit (sigma) dimethyl sulfoxide DMSO (sigma). Diethyl nitrosamine DEN (Chishiai (Shanghai) chemical industry development Co., Ltd.), carbon tetrachloride CCL4 (Tianjin Fuyu Fine chemical industry Co., Ltd.), olive oil (Colon measuring Instrument (Shanghai) Co., Ltd.). C57BL/6 mice and nude mice used in the experiments were purchased from Beijing Huafukang Biotech GmbH. Cell lysate (sigma); microplate reader, BCA kit (sigma). Electrophoresis electrotransfer system (Bio-RAD). Antibodies GAPDH were purchased from Santa/Santa Cruz, mTOR, p-MTOR from proteintech, and the remaining antibodies from abcam. PVDF membrane (Millipore, Bedford, USA) incubation of secondary antibodies (LI-COR Biosciences, USA) post membrane exposure with an Odyssey two-color infrared fluorescence scanning imaging system. The kit used for immunohistochemical experiments was an immunohistochemical kit purchased from sequoia golden bridge (SP 9001).
Experimental example 1 cytotoxic Effect of Sertraline or fluoxetine in combination with Sorafenib
1. Experimental Material
Human liver cancer cell line: huh7.5.1, HepG 2.
Hepatocellular carcinoma targeted therapeutic drugs: sorafenib.
Serotonin reuptake inhibitors: sertraline, fluoxetine.
2. Experimental methods
2.1 Experimental treatment:
MTT assay cell proliferation activity: the master solutions of sertraline and fluoxetine solutions were prepared at 150mM concentration using DMSO, respectively, and stored at-80 ℃. Huh7.5.1 and HepG2 hepatoma cell lines were treated with Sorafenib (2.5. mu.M, 5. mu.M, 10. mu.M, 20. mu.M) alone, sertraline (2.5. mu.M) in combination with Sorafenib (5. mu.M), fluoxetine (5. mu.M) in combination with Sorafenib (5. mu.M), respectively, 48h with DMSO diluted to a working solution concentration of 20mM before use and added to the medium at the desired concentration with this working solution, using dimethyl sulfoxide at a concentration of 0.1% DMSO as a control. After 48h, the cell activity was measured by the MTT method: cells were incubated with medium containing MTT solution (5mg/ml) for 4h, then the medium was removed and formazan crystals were dissolved in 150uL of DMSO. Absorbance at 490nM was measured with a microplate reader.
Cell clone formation experiment: at a rate of 8X 10 per hole3HepG2 cell, 5X 103Huh7.5.1 cells were plated in 6-well plates and pooled at-80 ℃ in 150mM concentrations of sertraline and fluoxetine, respectively, in DMSO. The solution was diluted with DMSO to a working solution concentration of 20mM before use. The working solution was added to the medium at the desired concentration, and both the two hepatoma cell lines were treated with sertraline (2.5. mu.M) and sorafenib (5. mu.M) in combination, and with fluoxetine (5. mu.M) and sorafenib (5. mu.M) in combination, using dimethylsulfoxide at a concentration of 0.1% DMSO as a control, for 14 days, respectively. During this period, the medium and drug were changed every two days, the cells were gently washed with PBS, fixed with 4% paraformaldehyde for 20 minutes, stained with 0.5% crystal violet solution for 15 minutes, and then the plates were rinsed with tap water and photographed.
Western blot experiment: at a rate of 20X 10 per hole4HepG2 cell, 20X 104The amount of huh7.5.1 cells was seeded in 6-well plates and dosed the next day after seeding. The master solutions of sertraline and fluoxetine solutions were prepared at 150mM concentration using DMSO, respectively, and stored at-80 ℃.The medium was diluted with DMSO to a working solution concentration of 20mM before use, and the working solution was added to the medium at the desired concentration. Huh7.5.1 and HepG2 hepatoma cell lines were treated with combinations of trastuzumab (2.5. mu.M) and sorafenib (2.5. mu.M, 5. mu.M) in combination with fluoxetine (2.5. mu.M, 5. mu.M) and sorafenib (2.5. mu.M, 5. mu.M) for 48 hours using dimethyl sulfoxide (DMSO concentration of 0.1% as a control, and then lysed with cell lysates, and subjected to immunoblotting experiments after measuring the protein concentration by BCA method.
2.2, detection:
(1) MTT assay for changes in cell proliferative Activity
After 48h of experimental treatment, cell proliferation activity was measured using MTT and the combination index was calculated using the hough formula using CompuSyn software.
(2) Observation of cell clone formation
After 14 days of experimental treatment, the number of clones was observed using crystal violet staining.
(3) Western blot
After 48h of experimental treatment, total cell protein was extracted and subjected to Western blotting to detect β -Catenin, c-Myc (proliferation-related protein), p-ERK (proliferation-related protein), Bcl-xl (apoptosis-related protein), PARP (apoptosis-related protein), p-mTOR, p-AKT, AKT and GAPDH (as internal references).
3. Results of the experiment
As shown in FIGS. 1A-F, the relative proliferation ratio of HepG2 cells was less than 25% and that of Huh7.5.1 cells was less than 30% using sertraline (2.5. mu.M) in combination with sorafenib (5. mu.M); the clone number of HepG2 cell and Huh7.5.1 cell is less than 10 unit number; while the relative proliferation ratio of sorafenib (5 mu M) used alone to HepG2 and Huh7.5.1 cell strains reaches about 50%, the clone number of HepG2 cells reaches 40 unit numbers, and the clone number of Huh7.5.1 cells exceeds 30 unit numbers, which are all obviously higher than those of a combined drug group. Stating that sertraline and sorafenib are mixed at a ratio of 0.5: 1, compared with sorafenib which is singly used, the composition has more remarkable capacity of inhibiting the proliferation of liver cancer cells.
When fluoxetine (5 mu M) and sorafenib (5 mu M) are used in combination, the relative proliferation ratio of the HepG2 cell is lower than 30%, and the relative proliferation ratio of the Huh7.5.1 cell is lower than 35%; the number of HepG2 cell clones is about 20 unit number, and the number of Huh7.5.1 cell clones is about 5 unit number; the relative proliferation ratio of sorafenib (5 mu M) used alone to HepG2 and Huh7.5.1 cell strains reaches more than 60 percent; the number of HepG2 cell clones exceeded 40 unit numbers, and the number of Huh7.5.1 cell clones exceeded 20 unit numbers, all significantly higher than the combination. Illustrating that fluoxetine and sorafenib are present in a ratio of 1:1, compared with sorafenib which is singly used, the composition has more remarkable capacity of inhibiting the proliferation of liver cancer cells.
Moreover, the combination index CI of the combined medication of sertraline and sorafenib and the combination index CI of the combined medication of fluoxetine and sorafenib are both less than 1, which shows that the combined medication of the invention has good synergistic effect.
As shown in FIGS. 2A-D, in two liver cancer cell lines, the combination of sertraline and sorafenib or the combination of fluoxetine and sorafenib reduced the expression of c-Myc, p-ERK, Bcl-xl, PARP, p-mTOR, p-AKT and AKT proteins in HepG2 and Huh7.5.1 cells, which is consistent with the results of MTT experiments and colony formation experiments.
4. Conclusion
The combined medication of sertraline and sorafenib has a synergistic effect, and the combined medication of fluoxetine and sorafenib has a synergistic effect. The combined medicament can obviously inhibit the growth and proliferation of in-vivo hepatoma cell strains, and particularly has excellent effect of combined use of 2.5 mu M sertraline and 5 mu M sorafenib.
Experimental example 2 combination of sertraline or fluoxetine and sorafenib inhibits primary liver cancer growth in vivo
1. Constructing an animal model: constructing an animal model: male C57BL/6 mice of 6-8 weeks of age were divided into blank group, positive control group, sertraline group, fluoxetine group, sorafenib group, sertraline-combined sorafenib group, and fluoxetine-combined sorafenib group. Except for the blank group, the other group mice were intraperitoneally injected with Diethylnitrosamine (DEN) formulated with physiological saline (50mg/kg body weight) from the first week, 7 days later with the same dose of DEN again (DEN was injected three times in total), from the fourth week, orally administered with carbon tetrachloride (CCL4) every week, formulated with olive oil, as olive oil: CCL4 was formulated at a 4:1 volume ratio for each oral administration at a dose of 5ml/kg body weight twice a week until mice were sacrificed 22 weeks from the first injection of CCL 4.
2. Experimental methods
2.1 Experimental treatment: the primary liver cancer model is divided into a blank group, a positive control group, a sertraline group, a fluoxetine group, sorafenib, a sertraline combined sorafenib group and a fluoxetine combined sorafenib group, and administration is started at 14 weeks after CCL4 is applied for the first time: sertraline group (20mg/kg body weight, oral) once daily; fluoxetine group (10mg/kg body weight, oral) was administered once daily; sorafenib (20mg/kg body weight, oral); sertraline in combination with fluoxetine group [ sertraline (20mg/kg body weight, oral) + sorafenib (20mg/kg body weight, oral) ]; fluoxetine in combination with sorafenib [ fluoxetine (10mg/kg body weight, oral) + sorafenib (20mg/kg body weight, oral) ] once daily,
until the end of the experiment.
2.2, detection:
mice were sacrificed at week 25, tumor volume, number were determined and counted.
3. Results of the experiment
As shown in FIG. 3, in terms of tumor volume, compared with the positive control group, the single administration of sertraline, fluoxetine and sorafenib inhibits the tumor volume and reduces the number of tumors, and the combined administration of sertraline or fluoxetine and sorafenib respectively can further reduce the tumor volume and number. Specifically, the combined administration of sertraline and sorafenib according to the weight ratio of 1:1 can obviously reduce the number of tumors and the volume of the tumors compared with a single sertraline drug or a single sorafenib drug; the fluoxetine and the sorafenib are used together according to the weight ratio of 1:1, so that the number of tumors and the volume of the tumors can be reduced more obviously than the fluoxetine single drug or the sorafenib single drug.
4. Conclusion
Compared with the single use of sertraline or fluoxetine and sorafenib, the combined use of sertraline and sorafenib or the combined use of fluoxetine and sorafenib can more obviously inhibit the growth of tumors in vivo.
In conclusion, the serotonin reuptake inhibitor sertraline or fluoxetine can obviously inhibit the proliferation of liver cancer cells and prevent liver cancer in vivo, the combined drug of the serotonin reuptake inhibitor and sorafenib has a synergistic effect, and the anticancer effect of the combined drug is obviously superior to that of the independent use of the serotonin reuptake inhibitor sertraline, fluoxetine or sorafenib. The combined medicament can not only obviously inhibit the proliferation of liver cancer cells in vivo and in vitro, but also play a role in treating primary liver cancer in vivo, and has good application prospect.
Claims (10)
1. A combined medicament for treating liver cancer, which is characterized by comprising a serotonin reuptake inhibitor and an antitumor medicament which are prepared from unit preparations with the same or different specifications and are used for simultaneous or separate administration, and a pharmaceutically acceptable carrier;
the serotonin reuptake inhibitor is sertraline or fluoxetine, and/or the antitumor drug is sorafenib.
2. The combination of claim 1, wherein the combination is a combination for the treatment of hepatocellular carcinoma.
3. The combination according to claim 1, wherein the concentrations of sertraline and antineoplastic agent are 2.5 μ M and 5 μ M, respectively; or the mass ratio of the sertraline to the anti-tumor medicine is 1: 1.
4. The combination of claim 1, wherein the concentration ratio of the fluoxetine to the anti-tumor drug is (3.75-5 μ M):5 μ M, and the molar ratio is (0.75-1): 1.
5. The combination as claimed in claim 4, wherein the concentration ratio of fluoxetine and anti-neoplastic agent is 3.75 μ M:5 μ M or 5 μ M:5 μ M, and the molar ratio is 0.75:1 or 1: 1.
6. Use of the combination drug according to any one of claims 1 to 5 in the preparation of a drug for treating liver cancer, preferably, the drug for treating liver cancer is a drug for treating hepatocellular carcinoma.
7. Use of a serotonin reuptake inhibitor and an anti-tumor drug in the preparation of a combined drug for treating liver cancer, wherein the serotonin reuptake inhibitor is sertraline or fluoxetine, and/or the anti-tumor drug is sorafenib; preferably, the combination drug for treating liver cancer is a combination drug for treating hepatocellular carcinoma.
8. The use according to claim 7, wherein the concentrations of sertraline and antineoplastic agent are 2.5 μ M and 5 μ M, respectively; or the mass ratio of the sertraline to the anti-tumor medicine is 1: 1.
9. The combination according to claim 7, wherein the concentration ratio of fluoxetine to the antineoplastic agent is (3.75-5 μ M):5 μ M, and the molar ratio is (0.75-1): 1.
10. The combination of claim 9, wherein the fluoxetine and anti-neoplastic agent are present in a concentration ratio of 3.75 μ Μ:5 μ Μ or 5 μ Μ:5 μ Μ, and the molar ratio is 0.75:1 or 1: 1.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114010642A (en) * | 2021-07-21 | 2022-02-08 | 四川大学华西医院 | Pharmaceutical composition for treating KRAS mutant intestinal cancer and combined medicine thereof |
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| WO2019204154A1 (en) * | 2018-04-18 | 2019-10-24 | Reyoung Corporation | Compositions and methods for treating liver cancer |
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2020
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| CN103517708A (en) * | 2011-04-06 | 2014-01-15 | 科翟特蔻·布瑞克茨克 | Pharmaceutical composition |
| WO2019204154A1 (en) * | 2018-04-18 | 2019-10-24 | Reyoung Corporation | Compositions and methods for treating liver cancer |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114010642A (en) * | 2021-07-21 | 2022-02-08 | 四川大学华西医院 | Pharmaceutical composition for treating KRAS mutant intestinal cancer and combined medicine thereof |
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