Application of compound PGG as a synergistic enhancer for anti-cancer drugs and pharmaceutical composition comprising PGG

Abstract

The present invention relates to the field of cancer treatment, and specifically relates to the application of compound PGG as a synergistic enhancer for anti-cancer drugs and a pharmaceutical composition comprising PGG. The present invention provides the application of compound 1,2,3,4,6-O-galloylglucose as a synergistic enhancer for anti-cancer drugs, and provides an anti-tumor pharmaceutical composition having a synergistic effect. The pharmaceutical composition comprises erlotinib and compound 1,2,3,4,6-O-galloylglucose, and the effect of the pharmaceutical composition in treating tumors is significantly enhanced.

Description

Technical Field

[0001] The present invention relates to the field of cancer treatment, and specifically relates to the application of compound PGG as a synergistic enhancer for anti-cancer drugs and a pharmaceutical composition comprising PGG. Background of the Invention

[0002] Tyrosine kinase is an enzyme that participates in regulating cell growth, differentiation, and signal transduction. Abnormal tyrosine kinase activity is associated with the development and progression of various diseases, especially cancer. Tyrosine kinase inhibitors slow down or prevent the growth and spread of cancer cells by interfering with or inhibiting the tyrosine kinase enzyme activity within cancer cells. These drugs are usually targeted therapy drugs, which are more selective than traditional chemotherapy drugs and generally cause less damage to normal cells.

[0003] Erlotinib is a first-generation reversible tyrosine kinase inhibitor that can selectively bind to the ATP-binding site of the EGFR tyrosine kinase, thereby inhibiting the phosphorylation of EGFR and preventing the activation of downstream signaling pathways. Erlotinib was initially approved for advanced NSCLC that has failed conventional chemotherapy. In November 2005, the FDA approved the combination of erlotinib and gemcitabine for the treatment of locally advanced, unresectable, or metastatic pancreatic cancer. Although the treatment with erlotinib has shown good efficacy, studies have found that almost all tumors will eventually develop resistance to erlotinib through different mechanisms. Therefore, the development of a synergistic enhancer for erlotinib is crucial for the treatment effect of cancer patients.

[0004] 1,2,3,4,6-O-Pentagalloylglucose (PGG) is a gallotannin present in plants. It has the characteristics of polyhydroxy substances and has good solubility. The glycosyl part is composed of glucose molecules. It has a wide range of applications in the fields of food, medicine, and cosmetics, and can also be used as an antioxidant, which has the effect of preventing lipid oxidation in food and cosmetics. PGG exerts anti-tumor effects by inhibiting the cell cycle, promoting autophagy, and inducing apoptosis, but its use as a synergistic enhancer for tyrosine kinase inhibitors has not been reported. Summary of the Invention

[0005] The present invention discovers that the combination of PGG and erlotinib can improve the treatment effect on pancreatic cancer. Compound PGG can enhance the efficacy of the tyrosine kinase inhibitor erlotinib against pancreatic cancer.

[0006] The primary object of the present invention is to provide the application of compound 1,2,3,4,6-O-galloylglucose as a synergistic enhancer for anti-cancer drugs.

[0007] Preferably, the anti-cancer drug is a tyrosine kinase inhibitor.

[0008] The second object of the present invention is to provide an anti-tumor pharmaceutical composition with a synergistic effect, and the pharmaceutical composition comprises an anti-cancer drug and compounds 1, 2, 3, 4, 6-O-galloylglucose.

[0009] Preferably, the anti-cancer drug is a tyrosine kinase inhibitor.

[0010] Preferably, the tyrosine kinase inhibitor comprises one or more of imatinib, erlotinib, gefitinib, cetuximab, icotinib, osimertinib, erlotinib, sorafenib.

[0011] The third object of the present invention is to provide the application of the pharmaceutical composition in the preparation of anti-tumor drugs.

[0012] Preferably, the tumor is any one or more of pancreatic cancer, breast cancer, cervical cancer, ovarian cancer, lung cancer, leukemia, malignant lymphoma, multiple myeloma, thyroid cancer, nasopharyngeal cancer, meningioma, pituitary tumor, oral cancer, craniopharyngioma, thalamic and brainstem tumors, vascular tumors, intracranial metastases, liver cancer, gastric cancer, esophageal cancer, colorectal cancer, rectal cancer, colon cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer, bone cancer, malignant melanoma, glioma, skin cancer.

[0013] Preferably, the tumor is pancreatic cancer.

[0014] The beneficial effects of the present invention are as follows: The present invention provides the application of compounds 1, 2, 3, 4, 6-O-galloylglucose as a synergistic agent for anti-cancer drugs. And an anti-tumor pharmaceutical composition with a synergistic effect is provided, and the pharmaceutical composition comprises erlotinib and compounds 1, 2, 3, 4, 6-O-galloylglucose, and the effect of the pharmaceutical composition in treating tumors is significantly enhanced. Description of the Drawings

[0015] Figure 1 In Model 1, compound PGG enhances the effect of erlotinib in treating pancreatic cancer. Note: A is the three-dimensional picture of the drug dose-response after the combined intervention of PGG and erlotinib at different concentrations of PDO-#1 in Combenefit software; B is the three-dimensional picture of the drug synergistic effect after the combined intervention of PGG and erlotinib at different concentrations on PDO-#1 under the three models of LOEWE, HSA, and BLISS in Combenefit software; C is the drug synergy score and two-dimensional picture after the combined intervention of PGG and erlotinib at different concentrations on PDO-#1 under the four models of LOEWE, ZIP, HSA, and BLISS in the Synergfinder online tool.

[0016] Figure 2In Model 2, compound PGG enhances the efficacy of erlotinib in treating pancreatic cancer. Note: A is a three-dimensional picture of the drug dose-response after the combined intervention of PGG and erlotinib at different concentrations on PDO-#2 in the Combenefit software; B is a three-dimensional picture of the drug synergistic effect after the combined intervention of PGG and erlotinib at different concentrations on PDO-#2 under the three models of LOEWE, HSA, and BLISS in the Combenefit software; C is the drug synergistic score and two-dimensional picture after the combined intervention of PGG and erlotinib at different concentrations on PDO-#2 under the four models of LOEWE, ZIP, HSA, and BLISS in the Synergfinder online tool.

[0017] Figure 3 In Model 3, compound PGG enhances the efficacy of erlotinib in treating pancreatic cancer. Note: A is a three-dimensional picture of the drug dose-response after the combined intervention of PGG and erlotinib at different concentrations on PDO-#3 in the Combenefit software; B is a three-dimensional picture of the drug synergistic effect after the combined intervention of PGG and erlotinib at different concentrations on PDO-#3 under the three models of LOEWE, HSA, and BLISS in the Combenefit software; C is the drug synergistic score and two-dimensional picture after the combined intervention of PGG and erlotinib at different concentrations on PDO-#3 under the four models of LOEWE, ZIP, HSA, and BLISS in the Synergfinder online tool.

[0018] Figure 4 Effect of PGG combined with erlotinib on tumor growth in pancreatic cancer xenograft mice. Note: A, B, and C are the ex vivo photos of tumors, tumor weight statistical charts, and tumor growth curves of pancreatic cancer xenograft mice after treatment with PGG and erlotinib alone or in combination, respectively. Specific implementation manners

[0019] The embodiments of the present invention will be described in detail below in conjunction with the examples. The following examples are only used to illustrate the present invention and should not be construed as limiting the scope of the present invention. For those not specified in the examples, they are carried out under conventional conditions or the conditions recommended by the manufacturer. For the reagents or instruments not specified by the manufacturer, they are all conventional products that can be obtained through commercial purchase.

[0020] Example 1. Effect of PGG combined with erlotinib on the growth of pancreatic cancer organoids

[0021] 1. Digest fresh tumor tissue samples from pancreatic cancer patients at 37°C for about 60 minutes using collagenase. After terminating the digestion, filter the digestion product with a cell sieve, discard the supernatant after centrifugation, and seed the obtained tumor stem cells into a cell culture plate. After the matrix gel solidifies, add the culture medium to construct pancreatic cancer organoid models of three different patients in this way;

[0022] 2. After the organoids grow stably, perform drug intervention. After the organoids form a ring, add PGG at 0, 100 nM, 1 μM, 10 μM, 50 μM, 100 μM and erlotinib at 0, 10 nM, 100 nM, 1 μM, 10 μM, 100 μM;

[0023] 3. After 6 days, use a 3D cell viability detection kit to detect the activity of the organoids;

[0024] 4. Use combefit software to statistically analyze the results of the synergy experiment with three different scoring models respectively;

[0025] 5. Use the synergyfinder online tool to statistically analyze the results of the synergy experiment with three different scoring models respectively.

[0026] As Figures 1 - 3 shown, all three models indicate that the compound PGG and erlotinib have a synergistic effect, and the treatment with PGG combined with erlotinib can significantly inhibit the growth of pancreatic cancer tumors. The compound PGG can be used as a synergist for the tyrosine kinase inhibitor erlotinib to improve the treatment effect of pancreatic cancer.

[0027] Example 2. Effect of PGG combined with erlotinib on the growth of pancreatic cancer xenograft tumors in mice

[0028] 1. Isolate fresh pancreatic cancer patient tumor samples to about 3 mm, wrap them with high-concentration Matrigel and implant them under the armpits of NCG mice (Jiangsu Jicui Yakang Biotech Co., Ltd., #T001475). Observe the growth status of the mice and the tumor volume every week. When the tumor grows to about 1000 mm 3 , passage it, and perform drug intervention when it is passaged to the third generation; 3

[0029] 2. Drug grouping:

[0030] (1) Control group: Solvent intervention;

[0031] (2) PGG group: Gavage, 20 mg / kg / day;

[0032] (3) Erlotinib group: Gavage, 50 mg / kg / day;

[0033] (4) PGG combined with erlotinib group: PGG by gavage, 20 mg / kg / day; Erlotinib by gavage, 50 mg / kg / day;

[0034] 3. The time point of the first drug intervention is day 0. Observe the growth status of the mice every day and measure the tumor volume of the mice every two days. When the tumor of one mouse in the four groups reaches 1500 mm 3 ​All mice were sacrificed at [time], and the tumor volume was measured before sacrifice and the tumor weight was weighed after sacrifice to evaluate the effects of different treatment regimens on the tumor growth of pancreatic cancer xenograft mice.

[0035] The results are as Figure 4 shown. Compared with the control group, both PGG and erlotinib alone could inhibit the growth of pancreatic cancer xenograft tumors in mice; compared with erlotinib alone treatment, the inhibitory effect could be further enhanced after the combination treatment of PGG and erlotinib, that is, the compound PGG could be used as a synergist of the tyrosine kinase inhibitor erlotinib to improve the treatment effect of pancreatic cancer.

[0036] In summary, the present invention provides the use of compounds 1, 2, 3, 4, 6-O-galloylglucose as an anticancer drug synergist. And a pharmaceutical composition with a synergistic effect for anti-tumor is provided, the pharmaceutical composition comprising erlotinib and compounds 1, 2, 3, 4, 6-O-galloylglucose, and the effect of the pharmaceutical composition in treating tumors is significantly enhanced.

Claims

1. Use of a pharmaceutical composition in the preparation of an anti-pancreatic cancer drug, characterized in that: The pharmaceutical composition consists of compounds 1, 2, 3, 4, 6-O-galloyl glucose and erlotinib.

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