Application of isomaltotetraose and anti-cancer pharmaceutical composition

Abstract

The invention relates to the technical field of medicines, in particular to application of isomaltotetraose and an anti-cancer medicine composition. The isomaltotetraose can be used as a YWHAB inhibitor combined with an anti-metabolic anti-tumor drug and a cytotoxic anti-tumor drug, for example, the combination of FOLFOX chemotherapy and isomaltotetraose has an excellent treatment effect on YWHAB high expression type local development stage colorectal cancer. The medicines are combined to overcome the drug resistance caused by anti-metabolic anti-tumor medicines and cytotoxic anti-tumor medicines, so that the effects of inhibiting the proliferation of tumor cells and promoting the apoptosis of cancer cells are achieved.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and more particularly, to the application of isomaltotetraose and an anti-cancer drug composition. Background Art

[0002] Colorectal cancer (CRC), as an important challenge in the prevention and treatment system of malignant tumors, its increasing epidemiological burden has become a focus issue in the field of public health.

[0003] Although the pathogenic mechanism of CRC has not been fully elucidated, existing evidence indicates that its onset involves complex interactions between genetic susceptibility and environmental exposure. Established risk factors include: positive family history, chronic inflammatory bowel disease, excessive intake of red meat and processed meat products, metabolic syndrome (covering phenotypes such as diabetes and obesity), and alcohol dependence. From an anatomical perspective, rectal cancer, due to its special location adjacent to pelvic organs and neurovascular bundles, poses three challenges in its clinical diagnosis and treatment: high complexity of surgical operation, significant risk of postoperative complications (especially for low rectal cancer), and difficulty in controlling local recurrence, and these characteristics are particularly prominent in locally advanced rectal cancer (LARC).

[0004] According to the international diagnosis and treatment consensus, LARC specifically refers to an advanced lesion with the lower edge of the tumor ≤ 12 cm from the anal verge and no distant metastasis (M0), and it needs to meet any of the following imaging / pathological criteria: the primary focus infiltrates and breaks through the muscular layer and involves adjacent structures (c / pT3-4b), or there is metastasis in the mesorectum / pelvic lymph nodes (c / pN1-2). The tumor biological behavior at this stage has significant invasive characteristics, combined with the complex pelvic anatomical structure, making the traditional treatment mode face a bottleneck in efficacy.

[0005] Currently, the NCCN guidelines have established neoadjuvant therapy as the standard treatment plan for LARC. Its core mechanism is to achieve tumor downstaging through chemoradiotherapy, thereby increasing the radical resection rate. The focus of clinical research is on the optimization of chemotherapy regimens, and a sequential treatment plan based on 5-fluorouracil (abbreviated as 5-FU) has been formed, including the combined application with cytotoxic drugs such as oxaliplatin and irinotecan. However, about 20-30% of patients have chemotherapy resistance, manifested as insufficient tumor regression (TRG grade 3-4) or imaging progression, ultimately leading to local control failure and decreased survival benefit. The resistance mechanism involves molecular-level changes such as tumor microenvironment heterogeneity, polymorphism of drug-metabolizing enzymes, and abnormal activation of DNA damage repair pathways, but currently, there is still a lack of evidence-based medical support for salvage treatment strategies for drug-resistant patients.

[0006] In view of this, the present invention is specifically proposed. Summary of the Invention

[0007] The object of the present invention is to provide the application of isomaltotetraose and an anti-cancer drug composition. An embodiment of the present invention provides a new use of the application of isomaltotetraose, which can be used as a YWHAB inhibitor, and then can treat colon cancer, especially advanced colorectal cancer. Isomaltotetraose can also be combined with FOLFOX chemotherapy to have an excellent therapeutic effect on YWHAB-high-expression locally advanced colorectal cancer, and can overcome the drug resistance of this type of patient to chemotherapeutic drugs, so as to achieve the effect of inhibiting the proliferation of tumor cells and promoting the apoptosis of tumor cells.

[0008] The present invention is implemented as follows: In the first aspect, the present invention provides an application of isomaltotetraose in the preparation of a YWHAB inhibitor.

[0009] In the second aspect, the present invention provides an application of isomaltotetraose in the preparation of an anti-tumor drug.

[0010] In an alternative embodiment, the tumor is colorectal cancer; Preferably, the tumor is advanced colorectal cancer with high expression of YWHAB.

[0011] In the third aspect, the present invention provides an application of isomaltotetraose in the preparation of a drug for treating drug-resistant tumors.

[0012] In an alternative embodiment, the drug-resistant tumor is drug-resistant colorectal cancer; Preferably, the drug-resistant tumor is advanced colorectal cancer resistant to chemotherapy; Preferably, the drug-resistant tumor is advanced chemotherapy-resistant colorectal cancer with high expression of YWHAB.

[0013] In an alternative embodiment, the anti-tumor drug tolerated by the drug-resistant tumor is at least one of anti-metabolic anti-tumor drugs and cytotoxic anti-tumor drugs; Preferably, the anti-tumor drug tolerated by the drug-resistant tumor includes a combination of anti-metabolic anti-tumor drugs and cytotoxic anti-tumor drugs; Preferably, the anti-tumor drug tolerated by the drug-resistant tumor includes a combination of fluorouracil and platinum-based anti-cancer drugs; Preferably, the drug tolerated by the drug-resistant tumor is the drug used in the FOLFOX treatment regimen, and this drug includes 5-fluorouracil and oxaliplatin.

[0014] In the fourth aspect, the present invention provides an application of isomaltotetraose in the preparation of a drug for treating a tumor resistant to the drug in the FOLFOX treatment regimen.

[0015] Fifth aspect, the present invention provides an anti-cancer drug composition, which comprises isomaltotetraose, an anti-metabolic anti-tumor drug and a cytotoxic anti-tumor drug; Preferably, the anti-cancer drug composition comprises the isomaltotetraose, fluorouracil, a platinum-based anti-cancer drug and a calcium salt; Preferably, the anti-cancer drug composition comprises the isomaltotetraose, the fluorouracil, the platinum-based anti-cancer drug and the calcium salt; wherein, the mass ratio of the isomaltotetraose, the fluorouracil, the platinum-based anti-cancer drug and the calcium salt is: (18 - 22):(95 - 105):(2 - 3):(10 - 15). Specifically, when the above drugs are used, isomaltotetraose is (18 - 22) mg / kg, fluorouracil is (95 - 105) mg / kg, the platinum-based anti-cancer drug (such as oxaliplatin) is (2 - 3) mg / kg, and the calcium salt (such as calcium folinate) is (10 - 15) mg / kg.

[0016] The above mg / kg refers to the number of mg of the drug used per kg of the patient.

[0017] Preferably, the anti-cancer drug composition comprises the isomaltotetraose, the fluorouracil, the platinum-based anti-cancer drug and calcium folinate.

[0018] Sixth aspect, the present invention provides an application of the anti-cancer drug composition described in the foregoing embodiment in the preparation of a drug for treating drug-resistant tumors; Preferably, the drug-resistant tumor is advanced drug-resistant colorectal cancer with high expression of YWHAB; Preferably, the drug-resistant tumor is advanced drug-resistant colorectal cancer resistant to the chemotherapy regimen FOLFOX.

[0019] The present invention has the following beneficial effects: (1) Through research, it is found in the embodiments of the present invention that YWHAB is a key driving gene mediating colorectal cancer chemotherapy resistance, and then YWHAB can be used as a biomarker for detecting the effect of neoadjuvant chemotherapy for rectal cancer.

[0020] (2) Isomaltotetraose can block the binding of YWHAB to the ubiquitination E3 ligase β-Trcp, inhibit the activation of the Wnt / β-catenin signal and nucleotide metabolism, that is to say, isomaltotetraose can be used as a YWHAB inhibitor.

[0021] (3) Isomaltotetraose can treat tumors, especially can be used as a drug for treating locally advanced rectal cancer with high expression of YWHAB, and can further improve the chemotherapy effect of colorectal cancer with high expression of YWHAB, and has good application prospects.

[0022] (4)Isomaltotetraose can treat drug-resistant tumors. In particular, isomaltotetraose can be combined with antimetabolic anti-tumor drugs and cytotoxic anti-tumor drugs to have excellent therapeutic effects on locally advanced colorectal cancer with high expression of YWHAB, and can overcome the drug resistance of patients with this type to chemotherapy drugs, thereby achieving the effects of inhibiting tumor cell proliferation and promoting tumor cell apoptosis. Brief Description of the Drawings

[0023] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required for use in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of the present invention, and therefore should not be regarded as a limitation of the scope. For those of ordinary skill in the art, without creative efforts, other related drawings can also be obtained based on these drawings.

[0024] Figure 1 For the test results of Example 1; among them, A is the screening flow chart of the key driver gene YWHAB mediating colorectal cancer chemotherapy resistance; B-C are the immunohistochemical staining (IHC) and scoring of YWHAB in tissue samples of colorectal cancer tissue microarray chips (TMA); D-E are the survival prognosis analysis of colorectal cancer patients with high and low expression of YWHAB; F-H are the expression levels of YWHAB in tumor tissues of rectal cancer patients with sensitive and drug-resistant neoadjuvant chemotherapy (biopsy specimens collected by colonoscopy before treatment) and the analysis of the treatment response rate of neoadjuvant chemotherapy in rectal cancer patients with high / low expression of YWHAB; Figure 2 For the test results of Example 2; among them, A is the construction process of the chemoresistant DLD-1 cell line; B is the treatment effect of different doses of FOLFOX chemotherapy on wild-type and drug-resistant DLD-1 cell lines; C is the analysis result of the specific binding site of isomaltotetraose and the "pocket" of YWHAB (source Alpha Fold-3); D is the virtual screening of inhibitors of YWHAB through the drug library of MCE Company, and DS is the binding energy (Docking Score); E is the protein expression level and statistical result of YWHAB in wild-type DLD-1 and chemoresistant DLD-1 cells; F-G are the treatment effects of FOLFOX combined with isomaltotetraose and bletilla striata glycoside in wild-type and drug-resistant DLD-1 cells respectively; H-I are the treatment effects of FOLFOX combined with isomaltotetraose in colorectal cancer organoids with high expression of YWHAB; Figure 3Detection result graph for Example 3; wherein, A is the stable cell line of DLD-1 drug-resistant cells with knocked-down YWHAB; B-D are the cell viability and spheroid formation ability of the YWHAB-knockdown group and the control group of DLD-1 drug-resistant cell lines treated with FOLFOX chemotherapy. Figure 4 Detection result graph for Example 4; wherein, A-B are the tumor volume and tumor weight of YWHAB-high-expression colorectal cancer PDX treated with PBS control group, FOLFOX, isomaltotetraose, and isomaltotetraose combined with FOLFOX. Detailed implementation manners

[0025] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. For those not specified in the embodiments, they are carried out according to conventional conditions or conditions recommended by the manufacturer. For reagents or instruments without indicating the manufacturer, they are all conventional products that can be obtained through commercial purchase.

[0026] YWHAB (also known as 14-3-3β) is a regulatory protein belonging to the 14-3-3 protein family and is widely involved in cell signal transduction, metabolic regulation, and the disease occurrence process. The embodiments of the present invention have found through research that YWHAB is a key driver gene mediating colorectal cancer chemotherapy resistance, and then YWHAB can be used as a biomarker for detecting the effect of neoadjuvant chemotherapy for rectal cancer.

[0027] Furthermore, the embodiments of the present invention have found that isomaltotetraose can block the binding of YWHAB to the ubiquitination E3 ligase β-Trcp, inhibit the activation of the Wnt / β-catenin signal, and nucleotide metabolism. Therefore, the embodiments of the present invention provide an application of isomaltotetraose as a YWHAB inhibitor.

[0028] Furthermore, the embodiments of the present invention have found that isomaltotetraose can treat tumors, especially as a drug for treating locally advanced rectal cancer with high expression of YWHAB, which can further improve the chemotherapy effect of colorectal cancer with high expression of YWHAB and has good application prospects. At the same time, the reagent for knocking down YWHAB can be used to improve the sensitivity of drug-resistant cell lines to FOLFOX chemotherapy.

[0029] Furthermore, the embodiments of the present invention also found that isomaltotetraose can treat chemotherapy-resistant tumors. In particular, isomaltotetraose can be combined with anti-metabolic anti-tumor drugs and cytotoxic anti-tumor drugs. For example, the combination of FOLFOX chemotherapy and isomaltotetraose has excellent therapeutic effects on locally advanced colorectal cancer with high expression of YWHAB, can overcome the drug resistance of patients with this type to chemotherapy drugs, and thus achieve the effects of inhibiting the proliferation of tumor cells and promoting the apoptosis of tumor cells.

[0030] That is, the embodiments of the present invention also provide an anti-cancer drug composition, which includes isomaltotetraose, anti-metabolic anti-tumor drugs and cytotoxic anti-tumor drugs. Further, the anti-cancer drug composition includes the isomaltotetraose, fluorouracil, platinum anti-cancer drugs (such as oxaliplatin) and calcium salts (such as calcium folinate); wherein, the mass ratio of isomaltotetraose, fluorouracil, platinum anti-cancer drugs and calcium salts is: (18-22):(95-105):(2-3):(10-15); specifically, when the above drugs are used, isomaltotetraose is (18-22) mg / kg, fluorouracil is (95-105) mg / kg, platinum anti-cancer drugs (such as oxaliplatin) are (2-3) mg / kg, and calcium salts (such as calcium folinate) are (10-15) mg / kg. For example, the in-vivo drug concentrations are respectively: isomaltotetraose 20 mg / kg, fluorouracil 100 mg / kg, oxaliplatin 2.5 mg / kg, and calcium folinate 12.5 mg / kg. This anti-cancer drug composition can treat tumors, especially locally advanced colorectal cancer with high expression of YWHAB.

[0031] The features and properties of the present invention will be further described in detail below in conjunction with embodiments.

[0032] Example 1 YWHAB is used to predict the chemosensitivity of rectal cancer Combined with biological characteristic information in multiple aspects such as copy number variation, whole transcriptomic gene matrix, protein expression level analysis, and survival prognosis analysis in public databases, the results are shown in Figure 1 Figure A, according to Figure 1 Figure A, it can be seen that the key driver gene YWHAB mediates the chemotherapy resistance of colorectal cancer.

[0033] The expression of YWHAB in patient samples was detected by immunohistochemical staining (IHC) using an anti-YWHAB antibody (Abcam, ab314175). The specific procedure was as follows: Paraffin sections were dewaxed by soaking in xylene and hydrated with gradient ethanol (100% - 95% - 80% - 60% - H2O), then microwave antigen retrieval was performed (prepared with 10 mM sodium citrate, 0.05% Tween 20, pH 6.0, placed in a microwave oven at high heat for 5 minutes and medium-low heat for 20 minutes), and cooled to room temperature. Endogenous peroxidase was blocked with 0.3% hydrogen peroxide for 10 minutes at room temperature, and blocked with goat serum blocking solution at 37°C for 30 minutes. The primary antibody (anti-YWHAB, Abcam, ab314175) was diluted 1:300 and incubated overnight at 4°C, the secondary antibody was incubated at 37°C for 30 minutes, and then stained with 3,3'-diaminobenzidine (DAB). In addition, rabbit IgG was used as the primary antibody, and the above operations were performed synchronously to obtain a negative control.

[0034] The expression of YWHAB was detected in normal and tumor tissue samples of colorectal cancer patients (the specific operation was as described above). The results are shown in Figure 1 Figures 1B - E. According to Figures 1B - E, YWHAB was highly expressed in tumor tissues, and it was suggested that the prognosis of colorectal cancer patients with high expression of YWHAB in tumor tissues was significantly worse.

[0035] In addition, based on the regression of rectal tumors before and after neoadjuvant FOLFOX chemotherapy, patients with a postoperative tumor pathological stage of ypStage 0 - I were defined as chemotherapy-sensitive patients, and patients with a postoperative tumor pathological stage of ypStage II - III were defined as chemotherapy-resistant patients. The expression of YWHAB was detected in tumor tissues of rectal cancer patients sensitive and resistant to neoadjuvant chemotherapy (biopsy specimens collected by colonoscopy before treatment) (the specific operation was as described above). The results are shown in Figures 1F - H. According to Figure 1 Figures 1F - H, the expression of YWHAB was significantly increased in tumor tissues of rectal cancer patients resistant to neoadjuvant chemotherapy. The above results indicate that YWHAB can be used as a biomarker to predict the efficacy of neoadjuvant chemotherapy for rectal cancer.

[0036] Example 2 Screening of YWHAB inhibitors and verification of the inhibitor combined with FOLFOX chemotherapy regimen Construction of chemotherapy-resistant DLD-1 cells: Wild-type DLD-1 cells were treated with fluorouracil (15 μM) and oxaliplatin (5 μM) at concentrations close to the IC50. After 7 days, the surviving DLD-1 cells were trypsinized and seeded into new cell culture dishes. When the density of DLD-1 cells reached 60 - 80%, the cells were treated with fluorouracil and oxaliplatin at twice the above concentrations. After 7 days, the surviving DLD-1 cells were trypsinized again and seeded into new cell culture dishes. And so on, by continuously increasing the treatment concentrations of fluorouracil and oxaliplatin, a drug-resistant cell line was induced ( Figure 2 as shown in A). After the successful construction of DLD-1 drug-resistant cells, we treated wild-type and drug-resistant DLD-1 cells with low-dose FOLFOX (fluorouracil 7.5 μM, oxaliplatin 2.5 μM), medium-dose FOLFOX (fluorouracil 60 μM, oxaliplatin 20 μM), and high-dose FOLFOX (fluorouracil 300 μM, oxaliplatin 100 μM): Low-dose FOLFOX could effectively kill wild-type DLD-1 cells, while high-dose FOLFOX could only slightly kill drug-resistant DLD-1 cells ( Figure 2 as shown in B).

[0037] Based on the MCE Bioactive Compound LibraryPlus (HY-L001P, an MCE bioactive compound database containing 26,780 bioactive compounds), a small molecule inhibitor library was constructed for the interaction structure between YWHAB and β-Trcp proteins. Virtual screening of drug-binding affinity was performed for the "binding pocket" of β-Trcp on the YWHAB protein. Combining the above small molecule inhibitor library, the binding ability of compounds to the interaction sites of the "binding pocket" on the YWHAB protein was calculated. The drug with the strongest binding ability to the "binding pocket" on the YWHAB protein was isomaltotetraose ( Figure 2 as shown in C - D). Western blot experiments demonstrated that the protein expression level of YWHAB was significantly increased in chemotherapy-resistant DLD-1 cells ( Figure 2 as shown in E).

[0038] In the cell proliferation experiment, the cells were digested and dispersed to form a single-cell suspension, counted using a cell counting chamber, and a certain number of cells (1000 - 2000 cells / well) were seeded into a 96-well white plate, with 3 replicate wells assigned to each treatment group. The next day, the medium was replaced with the medium containing the drug, and the cells were cultured at 37 °C for 4 days. Then, MTT solution (20 μL / well, Sigma) was added and incubated at room temperature for 2 hours. Subsequently, the medium was removed, and the cells were dissolved with DMSO (Sigma). Finally, the absorbance at 490 nm was measured using a microplate spectrophotometer (Thermo Scientific) to detect cell viability.

[0039] By detecting the activities of DLD-1 cells treated respectively with isomaltotetraose (100 μM) and bletilla striata glycoside (150 μM) in combination with FOLFOX chemotherapy (fluorouracil 7.5 μM, oxaliplatin 2.5 μM), and comparing with the cell activities of the PBS control group, isomaltotetraose monotherapy group, bletilla striata glycoside monotherapy group, and FOLFOX treatment group, the best drug combination with the combined drug effect was obtained. The results are shown in F - G of Figure 2, which are the results of detecting the activities of wild-type and chemotherapy-resistant DLD-1 cells treated with isomaltotetraose and bletilla striata glycoside in combination with the FOLFOX regimen respectively: isomaltotetraose is the best drug for reversing FOLFOX chemotherapy resistance, while bletilla striata glycoside cannot reverse chemotherapy resistance. The results are shown in Figure 2 H - I, which shows that the results of treating colorectal cancer organoids with isomaltotetraose (200 μM) in combination with FOLFOX chemotherapy (fluorouracil 20 μM, oxaliplatin 10 μM) once again verified the therapeutic effect of this drug combination regimen.

[0040] Example 3 Effect of YWHAB on the efficacy of FOLFOX chemotherapy regimen against DLD-1 drug-resistant cell line As shown in A of Figure 3, shRNA was used to knockdown YWHAB in drug-resistant DLD-1 cells, and the cell activities of the control group and the YWHAB knockdown group of DLD-1 drug-resistant cell lines after treatment with FOLFOX chemotherapy (fluorouracil 30 μM, oxaliplatin 10 μM) were detected respectively, so as to obtain the effect of YWHAB on the efficacy of the FOLFOX chemotherapy regimen. The results are shown in Figure 2 ) to obtain the effect of YWHAB on the efficacy of the FOLFOX chemotherapy regimen. The results are shown in Figure 3 B, which are the results of detecting the cell activities of the control group and the YWHAB knockdown group of DLD-1 drug-resistant cell lines treated with FOLFOX drug respectively: knockdown of YWHAB can significantly improve the sensitivity of drug-resistant DLD-1 cell lines to FOLFOX chemotherapy.

[0041] The 3D cell spheroid formation experiment can be achieved by the low-attachment plate method: Select a low-adsorption U-bottom culture plate with a specially treated surface to inhibit cell adhesion and growth. Add a single-cell suspension to each well at a density of approximately 5×10 3 ~ 1×10 4 cells, add serum-containing medium, and place it statically in an incubator at 37°C and 5% CO2 for culture. To accelerate spheroid formation, the cells can be centrifuged at 300×g for 5 minutes to promote cell aggregation, and then continue to culture for 24 - 72 hours. During this period, the cells form regular spheres through self-assembly, and the spheroid formation status is dynamically observed through an inverted microscope.

[0042] By detecting the 3D spheroid formation ability of DLD-1 drug-resistant cell lines after treatment with FOLFOX drugs (fluorouracil 60 μM, oxaliplatin 20 μM), the effect of YWHAB on the inhibition of spheroid formation of drug-resistant DLD-1 cell lines by the FOLFOX regimen was revealed. The results are shown in C-D of Figure 3. The 3D spheroid formation results of the FOLFOX chemotherapy-treated control group and the YWHAB knockdown group of DLD-1 drug-resistant cell lines were verified again: knocking down YWHAB can significantly improve the sensitivity of DLD-1 drug-resistant cell lines to FOLFOX chemotherapy.

[0043] Example 4 Effect of FOLFOX combined with isomaltotetraose on a mouse tumor-bearing model The purchased female BALB / c immunodeficient mice (nude mice, 5 - 8 weeks old) were first raised in the animal experiment center for 5 - 7 days. Two PDX models (PDX-CRC1, PDX-CRC2) derived from tumor tissues of YWHAB-high-expressing colorectal cancer patients were constructed, and the above PDX model mice were treated with PBS control solvent, FOLFOX (fluorouracil 100 mg / kg / day, oxaliplatin 2.5 mg / kg / day), isomaltotetraose (20 mg / kg / day), and FOLFOX combined with isomaltotetraose.

[0044] The results are shown in A-B of Figure 4. Treatment with FOLFOX chemotherapy combined with isomaltotetraose can effectively inhibit the growth of YWHAB-high-expressing colorectal cancer PDX tumors, indicating that in the YWHAB-high-expressing PDX model with chemotherapy resistance, the YWHAB inhibitor isomaltotetraose can enhance the therapeutic effect of FOLFOX chemotherapy, and at the same time suggesting that isomaltotetraose has the potential to be clinically applied to YWHAB-high-expressing colorectal cancer patients with chemotherapy resistance.

[0045] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and changes. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. Use of isomaltotetraose in the preparation of a YWHAB inhibitor.

2. Use of isomaltotetraose in the preparation of an anti-tumor drug.

3. The application according to claim 2, wherein The tumor is colorectal cancer; Preferably, the tumor is advanced colorectal cancer with high YWHAB expression.

4. Use of isomaltotetraose in the preparation of a drug for treating drug-resistant tumors.

5. The application according to claim 4, characterized in that The drug-resistant tumor is drug-resistant colorectal cancer; Preferably, the drug-resistant tumor is advanced chemotherapy-resistant colorectal cancer; Preferably, the drug-resistant tumor is advanced chemotherapy-resistant colorectal cancer with high YWHAB expression.

6. The application according to claim 4, wherein The anti-tumor drug to which the drug-resistant tumor is resistant is at least one of an anti-metabolic anti-tumor drug and a cytotoxic anti-tumor drug; Preferably, the anti-tumor drug to which the drug-resistant tumor is resistant includes a combination of an anti-metabolic anti-tumor drug and a cytotoxic anti-tumor drug; Preferably, the anti-tumor drug to which the drug-resistant tumor is resistant includes a combination of fluorouracil and a platinum-based anti-cancer drug; Preferably, the drug to which the drug-resistant tumor is resistant is 5-fluorouracil and oxaliplatin used in the FOLFOX treatment regimen.

7. Use of isomaltotetraose in the preparation of a drug for treating a tumor resistant to the drug in the FOLFOX treatment regimen.

8. An anti-cancer drug composition, characterized in that, It includes isomaltotetraose, an anti-metabolic anti-tumor drug, and a cytotoxic anti-tumor drug; Preferably, the anti-cancer drug composition includes the isomaltotetraose, fluorouracil, a platinum-based anti-cancer drug, and a calcium salt; Preferably, the anti-cancer drug composition includes the isomaltotetraose, the fluorouracil, the platinum-based anti-cancer drug, and the calcium salt; wherein, the mass ratio of the isomaltotetraose, the fluorouracil, the platinum-based anti-cancer drug, and the calcium salt is: (18 - 22):(95 - 105):(2 - 3):(10 - 15); Preferably, the anti-cancer drug composition includes the isomaltotetraose, the fluorouracil, the platinum-based anti-cancer drug, and calcium folinate.

9. Use of the anti-cancer drug composition according to claim 8 in the preparation of a drug for treating drug-resistant tumors.

10. According to the use described in claim 9, the drug-resistant tumor is advanced drug-resistant colorectal cancer with high YWHAB expression; Preferably, the drug-resistant tumor is advanced drug-resistant colorectal cancer resistant to the FOLFOX chemotherapy regimen.

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