CN114569728B - Composition, application and medicine thereof - Google Patents

Abstract

The invention relates to the technical field of medicines, and particularly discloses a composition, application and a medicine thereof. The compositions of the invention include an SGLT inhibitor and an inhibitor of tyrosine kinase activity. The present invention provides compositions comprising an SGLT inhibitor and an inhibitor of tyrosine kinase activity. Based on the inhibition effect of TKI targeting VEGFR, EGFR, HER2 and other receptor tyrosine kinases, the in vitro anti-tumor test shows that the combined administration of the SGLT inhibitors such as the sogliflozin, the SY-009, the Licogliflozin and the like and the tyrosine kinase activity inhibitor can produce a synergistic inhibition effect on tumors; but also can obviously enhance the curative effect of TKI drugs and reverse drug resistance, and can be used in the preparation of cancer treatment and anticancer drugs.

Description

Composition, application and medicine thereof

Technical Field

The invention relates to the technical field of medicines, in particular to a composition for treating cancers, and application and medicines thereof.

Background

1. Epidemiology of cancer

Non-infectious diseases are the main cause of death worldwide, while cancers are the diseases with the highest mortality rate among the non-infectious diseases, and bring heavy burden to the social health medical system. Traditional cancer treatment is mainly surgery and radiotherapy and chemotherapy, and for advanced cancer, chemotherapy is mainly used. Classical chemotherapy has large side effects due to poor targeting. The appearance of targeted chemotherapeutic drugs represented by Gliber greatly reduces the pain of patients caused by chemotherapy. Targeting drugs are designed for molecules that differ from normal cell growth characteristics and expression in cancer cells, such as glibenclamide Wei Teyi for constitutively activated tyrosine kinases in chronic myelogenous leukemia, thus achieving good therapeutic effects (Flynn and Gerriets, 2020). Another significant feature of cancer cells, which differ from normal cells, is the altered metabolic pattern. In order to balance the need for cellular components for rapid proliferation and to maintain the energy supply required for survival, cancer cells prefer to utilize glucose in a manner that uses aerobic glycolysis, which is known as the Warburg effect (Warburg, 1956). Aerobic glycolysis does not adequately oxidize glucose to produce ATP, but can produce large amounts of intermediate metabolites for DNA and protein synthesis to promote cancer cell proliferation. It is thus feasible to target the glycometabolism of tumor cells, thereby achieving the objective of inhibiting proliferation of cancer cells (Kroemer and Pouyssegur, 2008).

SGLT1 inhibitors and cancer treatment

The absorption of glucose by cancer cells from the external environment is mainly accomplished by glucose transporters, which are divided into two families, one is the GLUT family, which transports along the glucose concentration gradient by assisting diffusion, and the other is the sodium glucose transporter SGLT family, which absorbs glucose by co-transporting sodium ions, and which actively transports external glucose for use by cells in the form of ATP consumption (Navale and Paranjape, 2016). The two most prominent members of the SGLT family are SGLT1 and SGLT2, SGLT2 being distributed mainly at the front end of the proximal tubular of the kidney, and reabsorbing more than 97% of glucose in raw urine into blood by active transport, while SGLT1 is distributed mainly at the epithelial cells of the chorionic membrane of the small intestine and the distal end of the proximal tubular of the kidney, and absorbing glucose in the intestinal tract and about 3% of glucose remaining after absorption of SGLT2 in raw urine by active transport (Dominguez Rieg and Rieg, 2019). SGLT1 and SGLT2 are ideal targets for diabetes treatment due to their important roles in sugar absorption and reabsorption. Currently, the SGLT 2-targeted enggliflozin, canagliflozin and dapagliflozin are clinically used for treating type two diabetes mellitus, and have a good treatment effect and a treatment effect of reducing cardiovascular diseases. Miglitol targeting SGLT1 alone has entered the clinical study stage. SY-009 (Asian pharmaceutical industry) and Licogliflozin (Norhua pharmaceutical industry) targeting SGLT1 and SGLT2 simultaneously are marketed in European Union. There are also a number of SGLT inhibitors under investigation, and the use of these inhibitors in cancer has not been mentioned.

TKI and resistance of cancer to TKI

Receptor Tyrosine Kinases (RTKs) are the most common genes in cancer that promote cancer progression, and RTKs bind to the corresponding ligands and dimerize to catalyze autophosphorylation to initiate a series of downstream signaling cascades that promote cancer cell proliferation (Lemmon and Schlessinger,2010;Yarden and Pines,2012). Cancer cells often overexpress or constitutively activate RTKs and up-regulate RTK activity to promote self-proliferation, thus targeting RTK activity is a major tool for the development of anticancer drugs, including small molecule tyrosine kinase activity inhibitors (TKIs) targeting the ATP binding pocket of RTKs and monoclonal antibodies targeting ligand binding, etc. (Thomas and Weihua, 2019). The successful development of TKIs effectively prolonged by the overexpression of RTKs or the survival of constitutively activated patients without disease progression significantly improves the quality of life of the patients, most TKIs currently first-line in the relevant cancer field, however, except for cancer patients who are naturally resistant to TKIs, even patients who respond well to TKIs treatment develop acquired resistance within a treatment period of around one year (camridge et al; cortot and Janne, 2014). Summarizing the reasons for the development of resistance are mainly divided into pharmacological resistance, which is mostly caused by the inability of the drug to reach an effective concentration around cancer cells due to the interaction of the body drugs, which may remain sensitive to the drug, and biological resistance, which is caused by the development of drug-resistant mutations due to cancer heterogeneity, drug selection pressure, and alternative activation of bypass signaling pathways (mini, g., a et al). Biological resistance is the main cause of TKI drug resistance. For the mechanism of acquired resistance of cancer cells, researchers have devised a number of approaches to overcome the resistance of cancer, including the development of newer inhibitors for conventional resistance mutations, second generation, third generation, etc., in combination with radiation or chemotherapy and in combination with new targeted drugs after drug resistance. Even third generation inhibitors present acquired resistance to the current state, with little success in radiotherapy and chemotherapy. Overcoming drug resistance in combination with other targeting agents is the primary choice.

Disclosure of Invention

In view of the above, it is an object of the present invention to provide a composition such that a tyrosine kinase activity inhibitor (TKI) in the composition has a synergistic antitumor effect with an SGLT inhibitor;

another object of the present invention is to provide a composition, such that the tyrosine kinase activity inhibitor and the SGLT inhibitor in the composition can significantly enhance the therapeutic effect of TKI-type drugs and reverse the drug resistance;

it is another object of the present invention to provide the use of the above composition in the preparation of a medicament for treating cancer;

it is another object of the present invention to provide a medicament for treating cancer comprising the above composition;

in order to achieve the above purpose, the present invention provides the following technical solutions:

a composition for treating cancer comprising an SGLT inhibitor and an inhibitor of tyrosine kinase activity.

In the invention, the research shows that the proliferation speed of tumor cells in a low-sugar culture medium is reduced, and the sensitivity of TKI inhibitors such as lapatinib, apatinib, and tukatinib in the low-sugar culture medium is increased. Indicating that the low sugar enhances the sensitivity of the tumor cells to TKI drugs. At the same time, the lower cell density in the low-sugar medium suggests that low-sugar culture can also inhibit proliferation of cancer cells. In connection with the background art, the absorption of sugar by cancer cells is mainly dependent on SGLT family proteins, and thus the present invention thus contemplates that the combination of inhibitors of both will produce synergistic antitumor effects; experiments prove that the composition consisting of the tyrosine kinase activity inhibitor and the SGLT inhibitor has a remarkable inhibition effect on tumor growth, and the composition has a remarkable synergistic effect on tumor inhibition. Meanwhile, the drug-resistant tumor cell strain of the tyrosine kinase activity inhibitor can reverse the drug resistance after the composition is adopted, so that the curative effect of TKI drugs is obviously enhanced.

Accordingly, the present invention provides the use of the above composition in the preparation of a medicament for the treatment of cancer; such cancers include, but are not limited to, bladder cancer, blood cancer, bone cancer, brain cancer, breast cancer, central nervous system cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, gallbladder cancer, gastrointestinal cancer, external genital cancer, genitourinary tract cancer, head cancer, kidney cancer, laryngeal cancer, liver cancer, lung cancer, cancer of muscle tissue, neck cancer, oral or nasal mucosa cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, spleen cancer, small intestine cancer, large intestine cancer, stomach cancer, testicular cancer, and thyroid cancer.

Preferably, the molar ratio of the SGLT inhibitor to the tyrosine kinase activity inhibitor is (10 to 60): (5 to 60), more preferably (10 to 40): (5-60); in a specific embodiment of the invention, the molar ratio of SGLT inhibitor to tyrosine kinase activity inhibitor is 10:5, 10:10, 10:20, 10: 30. 10:40, 10:60, 20:5, 20:10, 20:20, 20: 30. 20:40, 20:60, 30:5, 30:10, 30:20, 30: 30. 30:40, 30:60, 40:5, 40:10, 40:20, 40: 30. 40:40 or 40:60.

In a specific embodiment of the invention, the invention performs a related test of the composition by means of concentration, wherein the concentration of 0 < SGLT inhibitor in the composition is less than or equal to 100 mu M, and the concentration of 0 < tyrosine kinase activity inhibitor in the composition is less than or equal to 100 mu M. In specific embodiments of the invention, the SGLT inhibitor concentration is 5, 10, 20, 30, 40, 60, 80, or 100 μm and the tyrosine kinase activity inhibitor concentration is 2.5, 5, 10, 20, 30, 40, 50, 60, 80, or 100 μm.

In a specific embodiment of the present invention, the SGLT inhibitor is selected from one or more of the group consisting of soligliflozin, SY-009 (purchased from the treasures pharmaceutical industry), and Licogliflozin (purchased from the nohua pharmaceutical industry);

preferably, the tyrosine kinase activity inhibitor is one or more selected from EGFR inhibitor, C-Kit inhibitor, C-Met inhibitor, C-Ret inhibitor, raf inhibitor, PDGFR inhibitor, BTK inhibitor, PKA/C inhibitor, FGFR inhibitor, VEGFR inhibitor, HER2 inhibitor.

Wherein the EGFR inhibitor is selected from one or more than two of gefitinib, erlotinib, afatinib, lapatinib xylene sulfonate, genistein, lapatinib, saptinib, daphnetin, dacatinib, valatinib, icotinib, lidocaine hydrochloride, olsterinib mesylate, olsterinib, wave Ji Tini, natatinib, AZD3759, omutinib, eweitinib, lenatinib and lasatinib;

the c-Met inhibitor is selected from cabotinib;

the PKA/C inhibitor is selected from daphnetin;

the BTK inhibitor is selected from the group consisting of armotinib;

the c-Ret inhibitor is selected from regorafenib hydrate and/or regorafenib;

the Raf inhibitor is selected from regorafenib hydrate;

the FGFR inhibitor is selected from one or more than two of 4- [ (1E) -2- [5- [ (1R) -1- (3, 5-dichloro-4-pyridyl) ethoxy ] -1H-indazol-3-yl ] vinyl ] -1H-pyrazole-1-ethanol, nidanib ethanesulfonate, panatinib, brianib and alanine brianib;

the c-Kit inhibitor is selected from one or more than two of acytinib, pazopanib hydrochloride, regorafenib hydrate, sunitinib malate, sunitinib, cetiratinib and tiratinib;

the PDGFR inhibitor is selected from one or more than two of acitinib, tivozanib, tilazanib, nilamide ethanesulfonate, pazopanib hydrochloride and panatinib;

the VEGFR inhibitor is selected from one or two of single or two anti-drugs of apatinib, acitinib, nilamide, ceritinib hydrochloride, sunitinib malate, britinib, cabotinib, alanine britinib, lenvatinib, regorafenib, ENMD-2076 tartrate, tivozanib, panatinib, furquitinib, tiratinib, douglas sonin, pazopanib, cabotinib malate, vitamin E, regorafenib hydrate, nilamide, lenvatinib mesylate, ceritinib maleate, 4- [ (1E) -2- [5- [ (1R) -1- (3, 5-dichloro-4-pyridyl) ethoxy ] -1H-indazol-3-yl ] vinyl ] -1H-pyrazole-1-ethanol, sunitinib, cetivatinib, an Luoti, sorafenib, deltalib, bevacizumab and the like;

the HER2 inhibitor is selected from one or more than two of lapatinib, lenatinib, sapatinib, wave Ji Tini, tucatinib, lapatinib xylene sulfonate and tucatinib.

In a specific embodiment of the present invention, the TKI-type drugs for verifying the efficacy of SGLT inhibitors in combination with tyrosine kinase activity inhibitors include: acxitinib, nilamide, cetirizine, pazopanib hydrochloride, sunitinib malate, britinib, cabitinib, alanine britinib, lenvatinib, regorafenib, ENMD-2076, tivozanib, panatinib, ENMD-2076 tartrate, tiratinib, douglas fir, pazopanib, cabatinib malate, vitamin E, regorafenib hydrate, nilamide ethanesulfonate, lenvatinib methanesulfonate, cetirizine maleate, and pharmaceutical compositions containing the same 4- [ (1E) -2- [5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ] -1H-indazol-3-yl ] vinyl ] -1H-pyrazole-1-ethanol, sunitinib, cetirizine, an Luoti, vandetanib, furquitinib, omrotigotine, olsterinib, genistein, ivertinib, dactinib, olsterinib mesylate, daphnetin, valatinib, AZD3759, lasatinib, nadatinib, lidocaine hydrochloride, icotinib, lapatinib, sapatinib, fleatinib, lapatinib, ditosylate, boscalid Ji Tini, and lenatinib.

According to the application provided by the invention, the invention also provides a medicament for treating cancer, which comprises the composition and pharmaceutically acceptable auxiliary agents.

Preferably, the pharmaceutical dosage form is a variety of dosage forms of oral medicaments, including but not limited to, granule, pill, powder, tablet, capsule, oral liquid, syrup, and the like.

Preferably, the capsule is a hard capsule or a soft capsule, and the tablet is an oral tablet or a buccal tablet.

The tablets refer to tablets for oral administration, and most of the drugs in such tablets are absorbed through the gastrointestinal tract to act, and some of the drugs in the tablets are locally acted on the gastrointestinal tract. In practical applications, the tablets may be ordinary compressed tablets, dispersible tablets, effervescent tablets, chewable tablets, coated tablets or sustained-release tablets.

Pharmaceutically acceptable adjuvants include, but are not limited to, fruit powders, flavoring essences, sweeteners, acidulants, fillers, lubricants, preservatives, suspending agents, food colors, diluents, emulsifiers, disintegrants, or plasticizers.

The invention also provides a method of treating cancer by administering the medicament of the invention.

From the above technical scheme, the invention provides a composition containing an SGLT1 inhibitor and a tyrosine kinase activity inhibitor. Based on the inhibition effect of TKI targeting VEGFR, EGFR, HER2 and other receptor tyrosine kinases, the in vitro anti-tumor test shows that the combined administration of the SGLT1 inhibitors such as the sogliflozin, the SY-009 and the Licogliflozin and the tyrosine kinase activity inhibitor can produce a synergistic inhibition effect on tumors; but also can obviously enhance the curative effect of TKI drugs and reverse drug resistance, and can be used in the preparation of cancer treatment and anticancer drugs.

Drawings

FIG. 1 shows the effect of the Apatinib and the SGLT inhibitor Licogliflozin on Hela cells; the value following the equal sign in each figure is the concentration value μM of Licogliflozin;

FIG. 2 shows the effect of apatinib and SGLT inhibitor SY-009 on HeLa cells; the value after the equal sign in each graph is SY-009 concentration value mu M;

SY-009 are shown in FIGS. 3-14 as well as Alxitinib (FIG. 3), nidatinib (FIG. 3), sidinebb (FIG. 3), pazopanib hydrochloride (FIG. 3), sunitinib malate (FIG. 4), britinib (FIG. 4), carbotinib (FIG. 4), ala Britinib (FIG. 4), levalatinib (FIG. 5), regorafenib (FIG. 5), ENMD-2076 (FIG. 5), tivozania (FIG. 5), panatatinib (FIG. 6), ENMD-2076 tartrate (FIG. 6), tiratinib (FIG. 6), doxolitinib (FIG. 6), pazopanib (FIG. 7), carbotinib malate (FIG. 7), vitamin E (FIG. 7), ruiganib hydrate (FIG. 7), nib ethanesulfonate (FIG. 8), levaltinib methanesulfonate (FIG. 8), sidindimaleate (FIG. 8), 4- [ (1E) -2- [5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl ] -Indonepwork (FIG. 9), vanilotinib (FIG. 9-9) Effects of combination of furatinib (fig. 10), omutinib (fig. 10), oltipinib (fig. 10), genistein (fig. 10), isotretinoin (fig. 11), dacatinib (fig. 11), oltipinib mesylate (fig. 11), daphnetin (fig. 11), valatinib (fig. 12), AZD3759 (fig. 12), lasatinib (fig. 12), nazatinib (fig. 12), lidocaine hydrochloride (fig. 13), icotinib (fig. 13), lapatinib (fig. 13), sapatinib (fig. 13), fig. 14), lapatinib xylene sulfonate (fig. 14), wave Ji Tini (fig. 14), and lenatinib (fig. 14); the value after the equal sign in each graph is SY-009 concentration value mu M;

figures 15-24 show Licogliflozin as shown in Nidaenib (figure 15), cilnidib (figure 15), pazopanib hydrochloride (figure 15), briminib (figure 15), carbotinib (figure 16), levalatinib (figure 16), regofil (figure 16), tivozania (figure 16), tizotinib (figure 17), dobanon (figure 17), pazopanib (figure 17), carbotinib malate (figure 17), vitamin E (figure 18), rutazopanib hydrate (figure 18), nidazopanesulfonate (figure 18), levatinib mesylate (figure 18), sidinibumaleate (figure 19), an Luoti Nib (figure 19), vade (figure 19), quetiatinib (figure 19), ozotinib (figure 20), oas (figure 20), titania (figure 20), ezotinib (figure 20), azotinib mesylate (figure 21), rumevalatinib (figure 21), lizotinib (figure 22), lizotinib (figure 23) and Motifoliatinib (figure 23 Effects of lenatinib (fig. 24) in combination; the value following the equal sign in each figure is the concentration value μM of Licogliflozin;

FIG. 25 shows the results of a test for reversing tumor cell resistance with a composition of the present invention.

Detailed Description

The invention discloses a composition, application and medicament thereof, and a person skilled in the art can properly improve the process parameters by referring to the content of the composition. It is expressly noted that all such similar substitutions and modifications will be apparent to those skilled in the art, and are deemed to be included in the present invention. While the compositions and uses and medicaments of the present invention have been described in terms of preferred embodiments, it will be apparent to those skilled in the relevant art that the compositions and uses and medicaments of the invention can be modified or adapted and combined to implement and use the present technology without departing from the spirit, scope and scope of the invention.

In a related test, the "efficacy" refers to the effect resulting from the treatment, expressed at the cellular level as an inhibition of cell growth or a cell death rate, expressed at the animal level as a change thereof, generally alleviating or ameliorating symptoms of a disease or condition, or curing a disease or condition, the invention uniformly taking a tumor growth inhibition of greater than 60% according to the drug effective guidelines while the statistical difference in tumor volume or weight p-value of the treated group versus the control group is less than 0.05.

"inhibition of cell growth" refers to the ratio of the mean absorbance of cells treated with the drug to the mean absorbance of cells treated with the control, and "inhibition of tumor growth" refers to the ratio of the mean tumor volume or weight of cells treated with the drug to the mean tumor volume or weight of cells treated with the control.

The drugs and their english names that may be involved in the embodiments are shown in table 1:

table 1 medicine and its English name

The composition provided by the invention and the application thereof as well as reagents or instruments used in the medicaments can be purchased from the market; the comparison experiments were performed with the exception of the differences that were due, and other experimental conditions were kept consistent for comparison, unless specifically indicated otherwise.

The invention is further illustrated by the following examples.

Example 1: SY-009 (Yabao pharmaceutical industry)/Licogliflozin (Norhua pharmaceutical) in combination with apatinib

1. Inhibition of tumor cells by combination (determination of IC50 value of combination)

The VEGFR inhibitor is an anti-angiogenesis inhibitor, if the drug resistance is not generated through an anti-vascular action theory, but is consistent with most targeting drugs, the drug resistance of the targeted VEGFR inhibitor also appears, and one possible reason is that the VEGFR inhibitor plays an anti-tumor role not only through inhibiting neovascularization, but also through targeting the VEGFR which is over-expressed by a tumor, so the invention is firstly verified by using a TKI drug of the targeted VEGFR, and according to the tissue distribution characteristics of the drug targets VEGFR and SGLT1/2 of the Apatinib and SY-009 (sub-Bakularch pharmaceutical industry)/Licoifilozin, the invention takes cervical cancer cell line Hela as an example for experimental verification. The method comprises the steps of growing cells to 80% density, digesting the cells by trypsin, passaging and spreading the cells in a 96-well plate, replacing the cells with a culture medium containing apatinib, SY-009 (Asian pharmaceutical industry), licogliflozin (North Hua pharmaceutical industry) and a combination of apatinib and SY-009 (Asian pharmaceutical industry)/Licogliflozin (North Hua pharmaceutical industry) at corresponding concentrations after 24 hours, and detecting the absorbance value at each concentration by using an MTT method after 48 hours.

The experiment is divided into:

control group: no medicine is added, and the method is only suitable for culturing cells in a normal culture medium;

apatinib test group: cells were treated with apatinib alone in the medium, and 8 different concentrations of treatment were set at 2.5. Mu.M, 5. Mu.M, 10. Mu.M, 20. Mu.M, 30. Mu.M, 40. Mu.M, 50. Mu.M, 60. Mu.M, respectively.

apatinib+sy-009/Licogliflozin combination test group: cells were treated with SY-009 or Licogliflozin and apatinib added to the medium.

Cell growth inhibition was calculated by dividing the absorbance at each concentration by the absorbance at the control, where the IC50 measured in the composition is the IC50 of the combination of apatinib at both different doses of the composition, as shown in figures 1 and 2. In fig. 1-2, the concentration of apatinib is taken as an abscissa, the cell growth inhibition rate is taken as an ordinate, and the result shows that the inhibition effect of the apatinib on tumor cells by the single use is limited, the inhibition rate of the apatinib on HepG2 cells is obviously enhanced along with the use of SY-009 or Licogliflozin and apatinib composition, the IC50 is reduced to less than one half of that of single drug, the combination of the two drugs is favorable for improving the inhibition effect on tumors, and the IC50 value of the apatinib can be obviously reduced by adding the SY-009/Licoglozin.

In addition, the invention also uses esophagus cancer cell line KYSE30, gastric cancer cell line HGC27, bile duct cancer cell line RBE, ovarian cancer cell line SKOV3, prostate cancer cell line DU145, breast cancer cell line MCF-7, liver cancer cell line QGY-7703, colorectal cancer cell line DLD1, SW480 and the like for experimental verification, and the results are shown in Table 2;

TABLE 2

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Note that: the concentration value mu M of SY-009/Licogliflozin is given after the equal sign;

the results in table 2 demonstrate that the ability of this combination to enhance the efficacy of a targeted VEGFR-like TKI is not limited to cervical cancer.

Example 2: verification of other TKI drugs

In this example, hepatoma cell line HepG2 was selected for experimental verification. The method comprises the steps of growing cells to 80% density, digesting the cells by trypsin, passaging and spreading the cells in a 96-well plate, replacing 5000 cells in each well after 24 hours with a culture medium containing tyrosine kinase activity inhibitors, SY-009 (Asian pharmaceutical industry), licogliflozin (North China medicine) and a combination drug of the tyrosine kinase activity inhibitors and SY-009/Licogliflozin at corresponding concentrations, and detecting the absorbance value at each concentration by using an MTT method after 48 hours.

The experimental procedure was the same as in the previous examples, with an incubation time of 1h. Experiments set a blank group, namely normal culture HepG2 cells, wherein the concentration of SY-009, licogliflozin or TKI drugs is 0, the survival rate of the cells in the blank group is 100%, the concentration of the SY-009 or Licogliflozin used in other administration groups is 60 mu M or 30 mu M, and the concentration of the TKI drugs is shown in the figure:

the results in fig. 3-24 show that in each drug combination group, the inhibition effect on tumor cells is good, and the effect is significantly better than that of the control group which is singly administered.

Example 3: reverse drug resistance test

The invention utilizes the culture medium containing the apatinib with gradually increased concentration to culture the QGY-7703 cells for a long time, so that the cells can obtain the drug resistance to the apatinib, and the invention obtains the QGY-7703 apatinib drug resistant cell strain which can survive in 35 mu M apatinib for a long time through 5 months of screening.

The apatinib-resistant cell strain obtained by the invention can still be effectively killed by adding 35 mu M of apatinib and 40 mu M of sogliflozin (S) composition. Whereas apatinib alone and sogliflozin had no effect at all on the drug-resistant cell line. The combination of Sogliflozin and Apatinib was demonstrated to reverse resistance of tumor cells to Apatinib, and the results are shown in FIG. 25.

The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.

Claims (5)

1. A composition comprising an SGLT inhibitor and an inhibitor of tyrosine kinase activity; the SGLT inhibitor is selected from SY-009; the tyrosine kinase activity inhibitor is selected from apatinib.

2. The composition according to claim 1, wherein the molar ratio of SGLT inhibitor to tyrosine kinase activity inhibitor is 10-60: 5-60.

3. Use of a composition according to any one of claims 1-2 for the preparation of a medicament for the treatment of cancer, including breast cancer, cervical cancer, colorectal cancer, esophageal cancer, liver cancer, ovarian cancer, prostate cancer, gastric cancer and cholangiocarcinoma.

4. A medicament for the treatment of cancer, comprising a composition according to any one of claims 1-2 and a pharmaceutically acceptable adjuvant.

5. The medicament according to claim 4, which is an oral medicament.