CN114010642A - Pharmaceutical composition for treating KRAS mutant intestinal cancer and combined medicine thereof - Google Patents
Pharmaceutical composition for treating KRAS mutant intestinal cancer and combined medicine thereof Download PDFInfo
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- CN114010642A CN114010642A CN202111595345.2A CN202111595345A CN114010642A CN 114010642 A CN114010642 A CN 114010642A CN 202111595345 A CN202111595345 A CN 202111595345A CN 114010642 A CN114010642 A CN 114010642A
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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Abstract
The invention provides a medicine composition for treating KRAS mutant intestinal cancer and a combined medicine thereof, and relates to the field of anti-cancer medicines. The pharmaceutical composition consists of a SERT inhibitor and a MEK inhibitor. The research of the invention shows that MEK inhibitors trametinib and SERT inhibitors sertraline have good inhibition effect on the proliferation of intestinal cancer cells, especially KRAS mutant intestinal cancer cells, the effect is obviously better than that of singly using the MEK inhibitors trametinib and SERT inhibitors sertraline, and the synergistic effect is exerted. The MEK inhibitor trametinib and SERT inhibitor sertraline can be used in a combined mode, can be prepared into a medicinal composition or a preparation, can be used for treating intestinal cancer, particularly KRAS mutant intestinal cancer, and has a good application prospect.
Description
Technical Field
The invention relates to the field of anti-cancer drugs, and in particular relates to a pharmaceutical composition for treating KRAS mutant intestinal cancer and a combined drug thereof.
Background
Intestinal cancer is one of the most common digestive tract malignancies, with morbidity and mortality rates at sites 3 and 4, respectively, of urban malignancies. Compared with other advanced malignant tumors of the digestive tract, the 5-year survival rate of the colorectal cancer patient is obviously improved due to the popularization of early diagnosis screening, the discovery of a new molecular target and the application of corresponding targeted drugs. The marketing of the targeted drug cetuximab has made great progress in the treatment of intestinal cancer, but about 50% of intestinal cancer patients have mutations in the KRAS gene, and these patients cannot benefit from cetuximab treatment, so that the treatment of intestinal cancer still faces great challenges. The search for a new mechanism and a potential new target point of intestinal cancer remains an important problem to be solved urgently in the clinical transformation research of intestinal cancer.
Trametinib (GSK1120212) is a novel allosteric small molecule oral MEK inhibitor that was approved by the FDA for use with dabrafenib in the treatment of BRAFV600E/K mutated unresectable/metastatic melanoma in 2013. In 2017, the protocol was approved for BRAFV600E mutant non-small cell lung cancer. In 2020, NCCN guidelines recommend dalafenib + trametinib + cetuximab for BRAF V600E mutant colorectal cancer patients. However, the research data is not particularly sufficient, and only the recommendation of class III experts is temporarily put into practice.
SERT (serotonin transporter) is encoded by SLC4A6 gene on human chromosome 17, and is Na+/Cl-Dependent transporters with 12 transmembrane poresStructure, internalization of 5-HT by sodium and chloride dependent means. Intestinal epithelial cells reabsorb 5-HT by SERT for recirculation and/or degradation to terminate signaling. Sertraline is a SERT inhibitor and a first-line clinical drug for the treatment of depression, and a number of epidemiological studies report that it is associated with a reduced risk of a number of tumors, including intestinal cancer, and have been demonstrated in a number of in vitro and in vivo studies.
However, the combined use of trametinib and sertraline has not been used to treat intestinal cancer, particularly KRAS mutant intestinal cancer.
Disclosure of Invention
The invention aims to provide a pharmaceutical composition for treating KRAS mutant intestinal cancer and a combined medicament thereof.
The invention provides a pharmaceutical composition for treating cancer, which consists of a SERT inhibitor and a MEK inhibitor.
Further, the SERT inhibitor is sertraline; the MEK inhibitor is trametinib.
Further, the molar ratio of the SERT inhibitor to the MEK inhibitor is (20-200): 1.
preferably, the molar ratio of the SERT inhibitor to the MEK inhibitor is (27-200): 1.
the invention also provides a method for preparing the pharmaceutical composition, which comprises the following steps: weighing SERT inhibitor and MEK inhibitor, and mixing.
The invention also provides the application of the pharmaceutical composition in preparing a medicament for treating cancer; preferably, the cancer is an intestinal cancer; more preferably, the cancer is KRAS mutant intestinal cancer.
The invention also provides a pharmaceutical preparation which is prepared by taking the pharmaceutical composition as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.
The invention also provides a combination for the treatment of cancer comprising a SERT inhibitor and a MEK inhibitor, administered simultaneously or separately, of the same or different specifications, and a pharmaceutically acceptable carrier.
Further, the SERT inhibitor is sertraline; the MEK inhibitor is trametinib.
Further, the mol ratio of the SERT inhibitor to the MEK inhibitor is (20-200): 1.
preferably, the molar ratio of the SERT inhibitor to the MEK inhibitor is (27-200): 1.
the invention also provides the application of the combined medicine in preparing a medicine for treating cancer; preferably, the cancer is an intestinal cancer; more preferably, the cancer is KRAS mutant intestinal cancer.
The research of the invention shows that MEK inhibitors trametinib and SERT inhibitors sertraline have good inhibition effect on the proliferation of intestinal cancer cells, especially KRAS mutant intestinal cancer cells, the effect is obviously better than that of singly using the MEK inhibitors trametinib and SERT inhibitors sertraline, and the synergistic effect is exerted. The MEK inhibitor trametinib and SERT inhibitor sertraline can be used in a combined mode, can be prepared into a medicinal composition or a preparation, can be used for treating intestinal cancer, particularly KRAS mutant intestinal cancer, and has a good application prospect.
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
FIG. 1 is a graph of the results of the synergistic inhibition of intestinal cancer cell proliferation in vitro of sertraline and trametinib: a is the synergy index of sertraline and trimetinib on SW480 cells; b is the combined inhibitory effect of sertraline (10 μ M) and trametinib (50nM) on SW480 cell proliferation; c is the synergy index of sertraline and trimetinib for HCT116 cells; d is the combined inhibitory effect of sertraline (10. mu.M) and trametinib (50nM) on HCT116 cell proliferation.
FIG. 2 shows the results of clone formation experiments for HCT116 cells and SW480 cells.
FIG. 3 shows the results of Western blotting of HCT116 cells and SW480 cells.
FIG. 4 is a graph of the combined tumor-inhibiting effect of sertraline and trametinib in nude mouse subcutaneous transplantation tumor models: a is the tumor entity map in the nude mice after the 13 th day of experiment; b is the increase of the tumor volume in the nude mice with time; c is the weight of the tumor in the nude mice after the 13 th day of experiment.
Detailed Description
The raw materials and equipment used in the embodiment of the present invention are known products and obtained by purchasing commercially available products.
Example 1 SERT inhibitors in combination with MEK inhibitors inhibit intestinal cancer cells in vitro
KRAS mutated human colon cancer cells: SW480(KRAS G12V), HCT116(KRAS G13D).
SERT inhibitors: sertraline (Sertra).
MEK inhibitors: trametinib (Trame).
1. Experimental methods
Grouping experiments: control group: treating the cells with DMSO; (xii) sertraline group, sertraline alone is used to treat cells; ③ trametinib group, using trametinib alone to treat cells; and (iv) a sertraline + trametinib group, wherein cells are treated by sertraline and trametinib simultaneously, and the molar ratio of sertraline to trametinib is 200: 1. Sertraline and trametinib were used as solutions prepared in DMSO at different concentrations.
(1) CCK8 detection of cell viability
Cells in logarithmic growth phase, SW480 and HCT116, were treated with different drugs:
control group: adding DMSO;
sertraline group (Sertra): adding sertraline with the concentration of 5 mu M, 10 mu M and 15 mu M respectively;
trametinib group (Trame): adding trametinib with the concentration of 25nM, 50nM and 75nM respectively;
sertraline + trametinib group (S + T): sertraline was added at a concentration of 5. mu.M and trametinib was added at a concentration of 25nM, or sertraline was added at a concentration of 10. mu.M and trametinib was added at a concentration of 50nM, or sertraline was added at a concentration of 15. mu.M and trametinib was added at a concentration of 75nM (the molar ratio of sertraline to trametinib was 200: 1).
The volume of drug added was the same for each group.
After the medicine is added, the cells are cultured for 2 days, then CCK8 is adopted to detect the cell activity, and the result utilizes Chou-Talalay formula to calculate the synergy index (CI), wherein CI <1 indicates that the two medicines have synergistic interaction.
(2) Observation of cell clone formation
The SW480 and HCT116 cells were clonally cultured by limiting dilution.
The cells were subjected to different drug treatments according to the group of "(1) CCK8 test for cell viability",
control group: adding DMSO;
sertraline group (Sertra): adding sertraline with the concentration of 15 mu M;
trametinib group (Trame): adding trametinib with the concentration of 75 nM;
sertraline + trametinib group (S + T): sertraline was added at a concentration of 15. mu.M and trametinib was added at a concentration of 75nM (the molar ratio of sertraline to trametinib was 200: 1).
The cells after the drug addition were cultured for 7 days, and after 7 days, the number of cell clones was observed by crystal violet staining.
(3) Western blot
Cells in logarithmic growth phase, SW480 and HCT116, were treated with different drugs: grouping according to (2) observing cell clonogenic "said:
control group: adding DMSO;
sertraline group (Sertra): adding sertraline with the concentration of 15 mu M;
trametinib group (Trame): adding trametinib with the concentration of 75 nM;
sertraline + trametinib group (S + T): sertraline was added at a concentration of 15. mu.M and trametinib was added at a concentration of 75nM (the molar ratio of sertraline to trametinib was 200: 1).
After 24h of cell culture, total cell protein was extracted and subjected to western blotting experiments to detect protein levels of c-Myc (proliferation-related protein), Cyclin D1 (cycle-related protein), PARP1 (apoptosis-related protein), BCL-XL (apoptosis-related protein) and GAPDH (as internal reference).
2. Results of the experiment
The experimental results show that: for both KRAS mutated HCT116 cells and SW480 cells, the relative cell proliferation ratios of sertraline + trametinib group were significantly lower than those of single drug sertraline and trametinib groups, and CI values were less than 1 (fig. 1), indicating that sertraline in combination with trametinib had a synergistic effect for the treatment of KRAS mutated intestinal cancer.
FIG. 2 shows the results of experiments on clone formation of HCT116 cells and SW480 cells, and it can be seen from FIG. 2 that the numbers of both cell clones in the sertraline + trametinib group are significantly less than those in the single-drug sertraline group and trametinib group. Indicating that the combination of sertraline and trametinib inhibits cell proliferation.
FIG. 3 shows the results of Western blotting of HCT116 cells and SW480 cells, and it can be seen from FIG. 3 that in both intestinal cancer cells, the combined administration of sertraline and trametinib significantly increased the expression of clear PARP1 and decreased the expression of BCL-XL and CyclinD1, which is consistent with the results of CCK8 and clonogenic experiments.
3. Conclusion
Compared with the single use of sertraline or trametinib, the combined use of sertraline and trametinib has a synergistic effect on the inhibition of KRAS mutant intestinal cancer cell proliferation, and has better ability of inhibiting KRAS mutant intestinal cancer cell proliferation.
Example 2 SERT inhibitors in combination with MEK inhibitors inhibit intestinal cancer cells in vivo
Intestinal cancer cell line: HCT116(KRAS G13D).
SERT inhibitors: sertraline.
MEK inhibitors: trametinib.
Constructing and grouping animal models: the intestinal cancer cell strain is transplanted into nude mice (BALB/c, 4-5 weeks, purchased from Beijing Huafukang Biotech, Ltd.) subcutaneously until the tumor is accessible (5 days after transplantation, the tumor volume in the mice is about 100mm3) Nude mice were randomly divided into 4 groups, which were a control group, a sertraline group, a trametinib group, and a sertraline + trametinib group, respectively.
1. Experimental methods
1.1 Experimental treatment: control group: namely a model group, the drug treatment is not used, and the physiological saline is used for replacing the treatment; (xii) sertraline group, with sertraline alone for treatment, 30mg/kg sertraline orally, once a day; ③ the trametinib group is used for treating by independently using trametinib, 2mg/kg of trametinib is injected into the abdominal cavity, and the treatment is carried out once a day; and (4) sertraline and trametinib, wherein sertraline and trametinib are used for simultaneous treatment, 30mg/kg of sertraline is orally taken, 2mg/kg of trametinib is intraperitoneally injected once a day, and the molar ratio of sertraline to trametinib is 27: 1. Administration was started on day 5 post-transplantation for 8 days (i.e., day 13 of the experiment), and then the mice were sacrificed for observation.
1.2 Experimental observations: nude mice were assayed for tumor volume transplanted every two days and animals were sacrificed in batches on day 13 of the experiment, tumors were removed and tumor size and volume were measured.
2. Results of the experiment
The tumors in nude mice at day 13 of the experiment are shown in FIG. 4A; the change in tumor volume in nude mice with increasing time of transplantation is shown in figure 4B; the tumor weights in nude mice at day 13 of the experiment are shown in figure 4C. As can be seen from fig. 4: the combined drug (sertraline and trametinib) group had the smallest tumor volume and the lightest weight; and the combined drug group has the slowest tumor growth trend. Compared with a control group and a single drug group, the combined drug group has the best inhibition effect on the in-vivo tumor growth.
3. Conclusion
Compared with the single use of sertraline or trametinib, the combined use of sertraline and trametinib has a synergistic effect on the inhibition of intestinal cancer tissues, and can play a more effective intestinal cancer inhibition role in vivo.
In conclusion, the research of the invention shows that MEK inhibitors trametinib and SERT inhibitors sertraline have good inhibition effect on the proliferation of intestinal cancer cells, especially KRAS mutant intestinal cancer cells, the effect is obviously better than that of singly using the MEK inhibitors trametinib and SERT inhibitors sertraline, and the synergistic effect is exerted. The MEK inhibitor trametinib and SERT inhibitor sertraline can be used in a combined mode, can be prepared into a medicinal composition or a preparation, can be used for treating intestinal cancer, particularly KRAS mutant intestinal cancer, and has a good application prospect.
Claims (10)
1. A pharmaceutical composition for treating cancer, comprising: it consists of a SERT inhibitor and a MEK inhibitor.
2. The pharmaceutical composition of claim 1, wherein: the SERT inhibitor is sertraline; the MEK inhibitor is trametinib.
3. The pharmaceutical composition of claim 1, wherein: the molar ratio of the SERT inhibitor to the MEK inhibitor is (20-200): 1.
4. a process for preparing a pharmaceutical composition according to any one of claims 1 to 3, characterized in that: it comprises the following steps: weighing SERT inhibitor and MEK inhibitor, and mixing.
5. Use of a pharmaceutical composition according to any one of claims 1 to 3 in the manufacture of a medicament for the treatment of cancer; preferably, the cancer is an intestinal cancer; more preferably, the cancer is KRAS mutant intestinal cancer.
6. A pharmaceutical formulation characterized by: the preparation is prepared by taking the pharmaceutical composition of any one of claims 1 to 3 as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.
7. A combination for the treatment of cancer, comprising: it contains a SERT inhibitor and a MEK inhibitor, which are administered simultaneously or separately, in the same or different specifications, and a pharmaceutically acceptable carrier.
8. The combination according to claim 7, wherein: the SERT inhibitor is sertraline; the MEK inhibitor is trametinib.
9. The combination according to claim 7, wherein: the mol ratio of the SERT inhibitor to the MEK inhibitor is (20-200): 1.
10. use of a combination according to any one of claims 7 to 9 in the manufacture of a medicament for the treatment of cancer; preferably, the cancer is an intestinal cancer; more preferably, the cancer is KRAS mutant intestinal cancer.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110826192 | 2021-07-21 | ||
| CN2021108261921 | 2021-07-21 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109646680A (en) * | 2019-01-31 | 2019-04-19 | 四川大学华西医院 | A kind of combination medicine for treating KRAS mutation type intestinal cancer |
| CN112190573A (en) * | 2020-11-17 | 2021-01-08 | 四川大学华西医院 | Combined medicine for treating liver cancer |
| CN112661657A (en) * | 2021-01-07 | 2021-04-16 | 中国人民解放军陆军军医大学 | Sertraline side chain amino structure derivative and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109646680A (en) * | 2019-01-31 | 2019-04-19 | 四川大学华西医院 | A kind of combination medicine for treating KRAS mutation type intestinal cancer |
| CN112190573A (en) * | 2020-11-17 | 2021-01-08 | 四川大学华西医院 | Combined medicine for treating liver cancer |
| CN112661657A (en) * | 2021-01-07 | 2021-04-16 | 中国人民解放军陆军军医大学 | Sertraline side chain amino structure derivative and preparation method and application thereof |
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| DI YE ET AL.: "《Targeting SERT promotes tryptophan metabolism: mechanisms and implications in colon cancer treatment》", 《JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH》 * |
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