Use of minocycline in the preparation of an antitumor potentiator

Abstract

The application belongs to the technical field of medicine, and relates to a use of minocycline in preparation of an antitumor synergist. The minocycline, as the antitumor synergist, has a synergistic effect with 5-fluorouracil and gemcitabine, significantly enhances the curative effect of an antitumor drug, reduces the dosage of the antitumor drug, and reduces side effects of the antitumor drug on the body or damage of the antitumor drug to normal tissue cells.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and relates to a use of minocycline in preparation of an antitumor synergist. BACKGROUND

[0002] Minocycline belongs to the second generation of tetracycline antibiotics, and has antibacterial spectrum covering gram-positive bacteria such as Staphylococcus aureus and Streptococcus pneumoniae, gram-negative bacteria such as gonococcus and meningococcus, mycoplasma, chlamydia, rickettsia, spirochete and part of anaerobes. The antibacterial mechanism is to combine with the 30S subunit of bacterial ribosomes, prevent aminoacyl-tRNA from combining with mRNA-ribosome complex, block peptide chain elongation and inhibit bacterial protein synthesis; mainly affects bacteria in the active growth period, and has bacteriostatic effect.

[0003] Pharmacological experiments prove that minocycline can inhibit matrix metalloproteinases (MMPs) involved in tumor invasion, metastasis and angiogenesis, and can reduce the damage of tumor cells to the surrounding tissues; reduce proinflammatory factors such as TNF-α, IL-1β and IL-6, inhibit the activation of microglial cells, play an anti-inflammatory role, and thus reduce the toxicity of antitumor drugs to normal tissues. The anti-tumor effect of minocycline is still in the research stage, and has not become part of the clinical standard treatment.

[0004] At present, there is no record of minocycline as an auxiliary drug for anti-tumor, reducing side effects or enhancing efficacy, and there is a great potential for developing minocycline as an anti-tumor synergist to meet the clinical treatment needs. SUMMARY

[0005] Based on the deficiencies in the prior art, the present application provides a use of minocycline in preparation of an antitumor synergist, enhances the efficacy of conventional antitumor drugs, effectively controls the dose of antitumor drugs, and reduces the side effects of high-dose antitumor drugs on the body or damage to normal tissue cells.

[0006] To achieve the above-mentioned purpose, the technical scheme of the present application is as follows:

[0007] The present application provides a use of minocycline in preparation of an antitumor synergist.

[0008] Further, the antitumor synergist and the antitumor drug synergistically act to improve the antitumor effect; the antitumor synergist is minocycline.

[0009] Further, the antitumor drug is selected from cisplatin, carboplatin, 5-fluorouracil, capecitabine and gemcitabine.

[0010] Further, the tumor is selected from liver cancer, lung cancer, bladder cancer, breast cancer, pancreatic cancer, rectal cancer and colon cancer.

[0011] Further, the antitumor is inhibiting tumor cell proliferation.

[0012] The application provides use of minocycline in preparation of an antitumor synergist, characterized in that the antitumor synergist is synergistic with an antitumor drug to improve antitumor effect; and the antitumor drug is 5-fluorouracil.

[0013] Further, the tumor is colon cancer.

[0014] Further, the antitumor is inhibiting HT-29 human colon cancer cell proliferation.

[0015] Further, the concentration of the minocycline is 0.1-40 μmol / L; and further, the concentration of the minocycline is 2.5, 5, 10, 17.3, 20, 40 μmol / L.

[0016] Further, the concentration of the 5-fluorouracil is 1-400 mg / L; and further, the concentration of the 5-fluorouracil is 25, 50, 100, 154.9, 200, 400 mg / L.

[0017] The application provides use of minocycline in preparation of an antitumor synergist, characterized in that the antitumor synergist is synergistic with an antitumor drug to improve antitumor effect; and the antitumor drug is gemcitabine.

[0018] Further, the tumor is breast cancer.

[0019] Further, the antitumor is inhibiting MDA-MB-231 human breast cancer cell proliferation.

[0020] Further, the concentration of the minocycline is 0.1-80 μmol / L; and further, the concentration of the minocycline is 5, 10, 20, 40, 44.1, 80 μmol / L.

[0021] Further, the concentration of the gemcitabine is 0.01-8 μmol / L; and further, the concentration of the 5-fluorouracil is 0.5, 1, 1.27, 2, 4, 8 μmol / L.

[0022] The application provides use of minocycline in preparation of an antitumor synergist, characterized in that the antitumor synergist is synergistic with an antitumor drug to improve antitumor effect; and the antitumor drug is 5-fluorouracil.

[0023] Further, the tumor is colon cancer.

[0024] Further, the antitumor is inhibiting HT-29 human colon cancer cell proliferation.

[0025] Further, the concentration of the minocycline is 0.1-40 μmol / L. Further, the concentration of the minocycline is 2.5, 5, 10, 17.3, 20, 40 μmol / L.

[0026] Further, the concentration of the 5-fluorouracil is 1-400 mg / L. Further, the concentration of the 5-fluorouracil is 25, 50, 100, 154.9, 200, 400 mg / L.

[0027] The application provides application of minocycline in combination with gemcitabine in preparation of an antitumor drug.

[0028] Further, the tumor is breast cancer.

[0029] Further, the antitumor is inhibition of MDA-MB-231 human breast cancer cell proliferation.

[0030] Further, the concentration of the minocycline is 0.1-80 μmol / L. Further, the concentration of the minocycline is 5, 10, 20, 40, 44.1, 80 μmol / L.

[0031] Further, the concentration of the gemcitabine is 0.01-8 μmol / L. Further, the concentration of the 5-fluorouracil is 0.5, 1, 1.27, 2, 4, 8 μmol / L.

[0032] Compared with the prior art, the application has the beneficial effects that minocycline as an antitumor synergist has a synergistic effect with 5-fluorouracil and gemcitabine, significantly enhances the curative effect of 5-fluorouracil and gemcitabine, and reduces the dosage of 5-fluorouracil and gemcitabine. The antitumor drug has certain toxicity to normal tissue cells of the human body, and the combination of minocycline and 5-fluorouracil for treating colon cancer and the combination of minocycline and gemcitabine for treating breast cancer can reduce the side effects of the high-dose antitumor drug on the body or the damage to normal tissue cells. DETAILED DESCRIPTION

[0033] The application will be further described below in combination with specific implementation examples, but the application is not limited to these examples.

[0034] Unless otherwise specified, the reagents, methods and devices used in the application are conventional reagents, methods and devices in the technical field. Unless otherwise specified, the reagents and materials used in the following examples are commercially available.

[0035] The minocycline used in the application is purchased from Shanghai Macklin Biochemical Technology Co., Ltd., with the article number M914100 and the CAS number 10118-90-8.

[0036] Example 1 Minocycline as a potentiator of anti-colon cancer drugs

[0037] HT-29 human colon cancer cell line (IMMOCELL, item number: IM-H102) was cultured in McCoy's medium containing 10% FBS, and the culture conditions were 95% air + 5% CO2, temperature 37°C.

[0038] HT-29 cells were treated with 0 (Control), 2.5, 5, 10, 20, 40 μmol / L of minocycline for 48 h, and 0 (Control), 25, 50, 100, 200, 400 mg / L of 5-fluorouracil (Abmole, item number: M2289, CAS: 51-21-8) for 48 h, and then the cell proliferation inhibition rate (%) at each concentration was detected by CCK-8 method, a curve was drawn, and the IC50 value was calculated. The IC50 value of minocycline-treated HT-29 cells for 48 h was about 17.3 μmol / L, and the IC50 value of 5-fluorouracil-treated HT-29 cells for 48 h was about 154.9 mg / L. The combination index CI value was calculated by CompuSyn software (CI>1 for antagonistic relationship between two drugs; CI<1 for synergistic relationship between two drugs, and the smaller the CI value, the stronger the synergistic effect), and the results are shown in Table 1.

[0039] Stably passaged HT-29 cells were divided into: blank control group, minocycline (10 μmol / L) group (MC group), 5-fluorouracil (100 mg / L) group (5-FU group), high-concentration minocycline (10 μmol / L) + 5-fluorouracil (100 mg / L) group (high MC + 5-FU group), and low-concentration minocycline (5 μmol / L) + 5-fluorouracil (50 mg / L) group (low MC + 5-FU group). The proliferation of cells in each group was detected by CCK-8 method, and the proliferation inhibition rate (%) = (test group OD value - cell-free drug-containing control group OD value) / (blank control group OD value - cell-free drug-free control group OD value) x 100%. The experimental data was analyzed by SPSS 17.0 software, and the results are shown in Table 2.

[0040] Table 1 CI value of minocycline and 5-fluorouracil

[0041]

[0042] The CI value calculated by TH-29 cell proliferation inhibition can determine that minocycline and 5-fluorouracil have a synergistic relationship, and the synergistic effect is stronger when minocycline is 10 μmol / L and 5-fluorouracil is 100 mg / L.

[0043] Table 2 Proliferation inhibition rate (%) of HT-29 cells in each group

[0044]

[0045] Note: compared with 5-FU group, *P<0.05;

[0046] The results of HT-29 cell proliferation inhibition rate showed that the high concentration minocycline (10 μmol / L) + 5-fluorouracil (100 mg / L) group (high MC + 5-FU group) had the best proliferation inhibition effect, and the inhibition effect was enhanced with the prolongation of action time. The low concentration minocycline (5 μmol / L) + 5-fluorouracil (50 mg / L) group (low MC + 5-FU group) could achieve the same proliferation inhibition effect as the 5-fluorouracil (100 mg / L) group (5-FU group), confirming that minocycline was a synergist of 5-fluorouracil. Since 5-fluorouracil has certain toxicity to normal cells, the combination of minocycline and 5-fluorouracil can reduce the dose of 5-fluorouracil and reduce the damage of antitumor drugs to the body.

[0047] Example 2 Minocycline as a synergist of anti-breast cancer drugs

[0048] MDA-MB-231 human breast cancer cell line (Shanghai Jianke Biological Technology Co., Ltd., Item No.: XK-XB-1416) was cultured in DMEM high glucose medium containing 10% FBS, and the culture conditions were 95% air + 5% CO2, temperature 37℃.

[0049] MDA-MB-231 cells were treated with 0 (Control), 5, 10, 20, 40, 80 μmol / L of minocycline for 48 h, and MIA PaCa-2 cells were treated with 0 (Control), 0.5, 1, 2, 4, 8 μmol / L of gemcitabine (solarbio, Item No.: G8970, CAS: 95058-81-4) for 48 h, and then the cell proliferation inhibition rate (%) under each concentration was detected by CCK-8 method, the curve was drawn, and the IC50 value was calculated. The IC50 value of minocycline treated MDA-MB-231 cells for 48 h was about 44.1 μmol / L, and the IC50 value of gemcitabine treated MDA-MB-231 cells for 48 h was about 1.27 μmol / L. The combination index CI value was calculated by CompuSyn software, and the results are shown in Table 3.

[0050] Stable passaged MDA-MB-231 cells were divided into: blank control group, minocycline (20 μmol / L) group (MC group), gemcitabine (1 μmol / L) group (GEM group), high concentration minocycline (20 μmol / L) + gemcitabine (1 μmol / L) group (high MC + GEM group), low concentration minocycline (10 μmol / L) + gemcitabine (0.6 μmol / L) group (low MC + GEM group). The proliferation of cells in each group was detected by CCK-8 method, and the inhibition rate (%) was calculated. The experimental data was analyzed by SPSS17.0 software, and the results were shown in Table 4.

[0051] Table 3 CI value of minocycline and gemcitabine

[0052]

[0053] The CI value calculated by MDA-MB-231 cell proliferation inhibition can determine the synergistic relationship between minocycline and gemcitabine.

[0054] Table 4 Inhibition rate (%) of MDA-MB-231 cell proliferation in each group

[0055]

[0056] Note: compared with GEM group, *P<0.05;

[0057] The results of MDA-MB-231 cell proliferation inhibition showed that the low concentration minocycline (10 μmol / L) + gemcitabine (0.6 μmol / L) group (low MC + GEM group) was slightly better than the gemcitabine (1 μmol / L) group (GEM group), which confirmed that minocycline was also a synergist of gemcitabine, and the combination of minocycline and gemcitabine could reduce the dose of gemcitabine.

[0058] The above describes the basic principles, main features and advantages of the present application. Those skilled in the art should understand that the present application is not limited to the above examples, and the above examples and descriptions in the specification are only the principles of the present application. Without departing from the spirit and scope of the present application, various changes and improvements can be made to the present application, and these changes and improvements all fall within the scope of the claimed present application. The scope of protection claimed by the present application is defined by the appended claims and their equivalents.

Claims

1. Use of minocycline in combination with 5-fluorouracil for the preparation of a medicament for the treatment of colon cancer, characterized in that, The minocycline in the anti-colon cancer drug is 10 μmol / L, and the 5-fluorouracil is 100 mg / L.

2. Use of minocycline in combination with gemcitabine for the preparation of a medicament against breast cancer, characterized in that, The minocycline in the anti-breast cancer drug is 20 μmol / L, and the gemcitabine is 1 μmol / L.

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