Application of minocycline in preparation of anti-tumor synergist

Abstract

The invention belongs to the technical field of medicines, and relates to application of minocycline in preparation of an anti-tumor synergist. The minocycline is used as an anti-tumor synergist and has a synergistic effect with the 5-fluorouracil and the gemcitabine, so that the curative effect of the anti-tumor medicine is remarkably enhanced, the dosage of the anti-tumor medicine is reduced, and the body side effect caused by the anti-tumor medicine or the damage to normal tissue cells is reduced.

Description

Technical Field

[0001] The invention belongs to the technical field of medicine and relates to the use of minocycline in preparing an anti-tumor synergist. Background Art

[0002] Minocycline is a second-generation tetracycline antibiotic with an antibacterial spectrum that covers Gram-positive bacteria such as Staphylococcus aureus and Streptococcus pneumoniae, Gram-negative bacteria such as gonococci and meningococci, mycoplasmas, chlamydiae, rickettsiae, spirochetes, and some anaerobic bacteria. Its antibacterial mechanism of action is binding to the 30S subunit of the bacterial ribosome, preventing the binding of aminoacyl-tRNA to the mRNA-ribosome complex, blocking peptide chain elongation and inhibiting bacterial protein synthesis. It primarily affects bacteria during their actively growing phase, exerting a bacteriostatic effect.

[0003] Pharmacological studies have confirmed that minocycline can inhibit matrix metalloproteinases (MMPs) involved in tumor invasion, metastasis, and angiogenesis, potentially reducing tumor cell damage to surrounding tissues. It also reduces pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6, inhibits microglial activation, and exerts anti-inflammatory effects, thereby reducing the toxicity of anti-tumor drugs to normal tissues. The anti-tumor effects of minocycline are still under investigation and have not yet become part of standard clinical treatment.

[0004] Currently, there is no record of minocycline as an auxiliary anti-tumor drug to reduce side effects or enhance therapeutic effects. There is an urgent need to develop the huge potential of minocycline as an anti-tumor enhancer to meet clinical treatment needs. Summary of the Invention

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

[0006] To achieve the above object, the technical solution of the present invention is achieved as follows:

[0007] The present invention provides use of minocycline in preparing an anti-tumor synergist.

[0008] Furthermore, the anti-tumor synergist acts synergistically with the anti-tumor drug to improve the anti-tumor effect; the anti-tumor synergist is minocycline.

[0009] Furthermore, the anti-tumor drug is selected from cisplatin, carboplatin, 5-fluorouracil, capecitabine, and gemcitabine.

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

[0011] Furthermore, the anti-tumor effect is the inhibition of tumor cell proliferation.

[0012] The present invention provides use of minocycline in preparing an antitumor synergist, which is characterized in that the antitumor synergist acts synergistically with an antitumor drug to improve the antitumor effect; the antitumor drug is 5-fluorouracil.

[0013] Furthermore, the tumor is colon cancer.

[0014] Furthermore, the anti-tumor effect is to inhibit the proliferation of HT-29 human colon cancer cells.

[0015] Furthermore, the concentration of minocycline is 0.1-40 μmol / L. Furthermore, the concentration of minocycline is 2.5, 5, 10, 17.3, 20, or 40 μmol / L.

[0016] Furthermore, the concentration of 5-fluorouracil is 1-400 mg / L. Furthermore, the concentration of 5-fluorouracil is 25, 50, 100, 154.9, 200, or 400 mg / L.

[0017] The present invention provides use of minocycline in preparing an antitumor synergist, which is characterized in that the antitumor synergist acts synergistically with an antitumor drug to improve the antitumor effect; the antitumor drug is gemcitabine.

[0018] Furthermore, the tumor is breast cancer.

[0019] Furthermore, the anti-tumor effect is to inhibit the proliferation of MDA-MB-231 human breast cancer cells.

[0020] Furthermore, the concentration of minocycline is 0.1-80 μmol / L. Furthermore, the concentration of minocycline is 5, 10, 20, 40, 44.1, or 80 μmol / L.

[0021] Furthermore, the concentration of gemcitabine is 0.01-8 μmol / L. Furthermore, the concentration of 5-fluorouracil is 0.5, 1, 1.27, 2, 4, or 8 μmol / L.

[0022] The present invention provides the use of minocycline in combination with 5-fluorouracil in the preparation of anti-tumor drugs.

[0023] Furthermore, the tumor is colon cancer.

[0024] Furthermore, the anti-tumor effect is to inhibit the proliferation of HT-29 human colon cancer cells.

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

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

[0027] The present invention provides the use of minocycline in combination with gemcitabine in the preparation of anti-tumor drugs.

[0028] Furthermore, the tumor is breast cancer.

[0029] Furthermore, the anti-tumor effect is to inhibit the proliferation of MDA-MB-231 human breast cancer cells.

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

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

[0032] Compared with existing technologies, the present invention has the following beneficial effects: minocycline, as an anti-tumor synergist, synergizes with 5-fluorouracil and gemcitabine, significantly enhancing the therapeutic efficacy of 5-fluorouracil and gemcitabine and reducing their dosage. Anti-tumor drugs are toxic to normal human tissue cells. Combining minocycline with 5-fluorouracil for the treatment of colon cancer and with gemcitabine for the treatment of breast cancer can reduce the side effects or damage to normal tissue cells caused by high-dose anti-tumor drugs. DETAILED DESCRIPTION

[0033] The present invention will be further described below with reference to specific implementation cases, but the present invention is not limited to these embodiments.

[0034] Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the art. Unless otherwise specified, the reagents and materials used in the following examples are commercially available.

[0035] The minocycline used in the present invention was purchased from Shanghai MacLean Biochemical Technology Co., Ltd. with the product number M914100 and the CAS number 10118-90-8.

[0036] Example 1 Minocycline as a synergist for anti-colon cancer drugs

[0037] HT-29 human colon cancer cell line (IMMOCELL, Catalog No.: IM-H102) was cultured in McCoy's medium containing 10% FBS in an atmosphere of 95% air + 5% CO2 at 37°C.

[0038] HT-29 cells were treated with minocycline at concentrations of 0 (Control), 2.5, 5, 10, 20, and 40 μmol / L for 48 h, and 5-fluorouracil (Abmole, Catalog No. M2289, CAS: 51-21-8) at concentrations of 0 (Control), 25, 50, 100, 200, and 400 mg / L for 48 h. Cell proliferation inhibition (%) at each concentration was determined using CCK-8 assay. Curves were plotted, and IC50 values ​​were calculated. The IC50 values ​​for minocycline and 5-fluorouracil were approximately 17.3 μmol / L and 154.9 mg / L, respectively, after treatment for 48 h. CompuSyn software was used to calculate the binding index (CI). The results are shown in Table 1.

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

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

[0041]

[0042] The CI value calculated by the inhibition of TH-29 cell proliferation confirmed that minocycline and 5-fluorouracil had a synergistic relationship, and the synergistic effect was stronger when the minocycline concentration was 10 μmol / L and the 5-fluorouracil concentration was 100 mg / L.

[0043] Table 2 HT-29 cell proliferation inhibition rate in each group (%)

[0044]

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

[0046] HT-29 cell proliferation inhibition results showed that the high-concentration minocycline (10 μmol / L) + 5-fluorouracil (100 mg / L) group (high MC + 5-FU group) exhibited the best inhibitory effect, which increased with prolonged exposure. The low-concentration minocycline (5 μmol / L) + 5-fluorouracil (50 mg / L) group (low MC + 5-FU group) achieved comparable inhibitory effects to the 5-fluorouracil (100 mg / L) group (5-FU group), confirming that minocycline is a potentiator of 5-fluorouracil. Because 5-fluorouracil has some toxicity to normal cells, the combination of minocycline and 5-fluorouracil can reduce the 5-fluorouracil dose and mitigate the damage caused by the anti-tumor drug to the body.

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

[0048] MDA-MB-231 human breast cancer cell line (Shanghai Xuanke Biotechnology Co., Ltd., catalog number: XK-XB-1416) was cultured in DMEM high-glucose medium containing 10% FBS in an atmosphere of 95% air + 5% CO2 at 37°C.

[0049] MDA-MB-231 cells were treated with minocycline at concentrations of 0 (Control), 5, 10, 20, 40, and 80 μmol / L for 48 hours, and MIA PaCa-2 cells were treated with gemcitabine (solarbio, Catalog No. G8970, CAS: 95058-81-4) at concentrations of 0 (Control), 0.5, 1, 2, 4, and 8 μmol / L for 48 hours. Cell proliferation inhibition (%) at each concentration was determined using the CCK-8 assay. Curves were plotted, and IC50 values ​​were calculated. The IC50 values ​​for minocycline treatment of MDA-MB-231 cells for 48 hours were approximately 44.1 μmol / L, and those for gemcitabine treatment of MDA-MB-231 cells for 48 hours were approximately 1.27 μmol / L. Binding indices (CIs) were calculated using CompuSyn software. The results are shown in Table 3.

[0050] Stably passaged MDA-MB-231 cells were divided into the following groups: a blank control group, a minocycline (20 μmol / L) group (MC group), a gemcitabine (1 μmol / L) group (GEM group), a high-concentration minocycline (20 μmol / L) + gemcitabine (1 μmol / L) group (high MC + GEM group), and a low-concentration minocycline (10 μmol / L) + gemcitabine (0.6 μmol / L) group (low MC + GEM group). Cell proliferation in each group was detected using the CCK-8 assay, and the proliferation inhibition rate (%) was calculated. The experimental data were analyzed using SPSS 17.0 software. The results are shown in Table 4.

[0051] Table 3 CI values ​​of minocycline and gemcitabine

[0052]

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

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

[0055]

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

[0057] The results of MDA-MB-231 cell proliferation inhibition rate 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), confirming that minocycline is also a synergist of gemcitabine, and the combination of minocycline and gemcitabine can reduce the dose of gemcitabine.

[0058] The above describes the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The above embodiments and description merely illustrate the principles of the present invention. Various changes and modifications may be made to the present invention without departing from the spirit and scope of the present invention. Such changes and modifications are intended to fall within the scope of the present invention. The scope of protection claimed by the present invention is defined by the appended claims and their equivalents.

Claims

1. Use of minocycline in the preparation of an antitumor synergist, characterized in that: The anti-tumor synergist acts synergistically with the anti-tumor drug to improve the anti-tumor effect.

2. The use according to claim 1, characterized in that The anti-tumor drug is selected from cisplatin, carboplatin, 5-fluorouracil, capecitabine, and gemcitabine.

3. The use according to claim 1, characterized in that The tumor is selected from liver cancer, lung cancer, bladder cancer, breast cancer, pancreatic cancer, rectal cancer, and colon cancer.

4. The use according to claim 1, characterized in that: The anti-tumor effect is to inhibit the proliferation of tumor cells.

5. The use according to claim 1, characterized in that: The concentration of minocycline is 0.1-80 μmol / L.

6. The use according to claim 2, characterized in that: The concentration of the 5-fluorouracil is 1-400 mg / L; the concentration of the gemcitabine is 0.01-8 μmol / L.

7. The use according to claim 4, characterized in that: The inhibition of tumor cell proliferation is the inhibition of HT-29 human colon cancer cell proliferation.

8. The use according to claim 4, characterized in that: The inhibition of tumor cell proliferation is the inhibition of MDA-MB-231 human breast cancer cell proliferation.

9. Use of minocycline in combination with 5-fluorouracil in the preparation of anti-tumor drugs, characterized in that: The tumor is colon cancer.

10. Use of minocycline in combination with gemcitabine in the preparation of an anti-tumor drug, characterized in that: The tumor is breast cancer.

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