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Application of a macrolide compound in reversing tumor multidrug resistance and enhancing antitumor efficacy

A multi-drug resistance, tumor technology, applied in anti-tumor drugs, medical preparations containing active ingredients, pharmaceutical formulations, etc. complex issues

Active Publication Date: 2022-03-18
FUJIAN MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the existing anticancer drugs are not ideal for tumor metastasis and drug resistance.
[0006] The formation mechanism of tumor drug resistance is complex, and the abnormal expression of ABC transporter is an important reason for the multidrug resistance of tumor cells, which has become the focus of drug resistance research in recent years

Method used

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  • Application of a macrolide compound in reversing tumor multidrug resistance and enhancing antitumor efficacy
  • Application of a macrolide compound in reversing tumor multidrug resistance and enhancing antitumor efficacy
  • Application of a macrolide compound in reversing tumor multidrug resistance and enhancing antitumor efficacy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Example 1 Compound Con enhances the in vitro antitumor effect of ABCB1 or ABCG2 substrate chemotherapeutic drugs on corresponding drug-resistant cells

[0031] 1.1 Material Description

[0032] Tumor cell lines: human oral cancer cell line KB and its ABCB1 overexpression cell line KBv200, human chronic myeloid leukemia cell line K562 and its ABCB1 overexpression cell line K562 / adr, human breast cancer cell line MCF-7 and its ABCB1 overexpression cell line Cell line MCF-7 / adr, human colon cancer cell line S1 and its ABCG2 overexpressing cell line S1-M1-80, human non-small cell lung cancer cell line H460 and its ABCG2 overexpressing cell line H460 / MX20, human embryonic kidney cancer Cell line HEK293 and its transfection empty vector cell line HEK293 / pcDNA3.1, ABCB1 stable transfection cell line HEK293 / ABCB1, ABCG2 stable transfection cell line HEK293 / ABCG2-R2. KBv200 cells were added with vincristine at a final concentration of 0.2 mg / L in the culture system, and K562 / ad...

Embodiment 2

[0045] Example 2 Compound Con enhances the in vivo antitumor effect of substrate chemotherapeutic drugs on ABCB1-mediated drug-resistant cells

[0046] 2.1 Materials

[0047] Human oral epithelial cancer vincristine-resistant cells KBv200, 5-6 weeks old BALB / C-nu nude mice, no special pathogenic bacteria (SPF) grade, male, purchased from Shanghai Slack Laboratory Animal Co., Ltd., production license License number: SCXK (Shanghai) 2012-0002; Laboratory animal breeding facility use license number: SYXK (Min 2016-0007).

[0048] 2.2 Methods

[0049] 2.2.1 Establishment of nude mouse KBv200 xenograft model

[0050] Collect 1×10 KBv200 cells in logarithmic growth phase 8 / mL, 3 nude mice were taken as breeding mice, and 0.2 mL of cell suspension was injected into each nude mouse subcutaneously in the right forelimb. After the tumor mass is formed, modeling is carried out, and the modeling process is carried out in a sterile operating table. Before modeling, the nude mice were...

Embodiment 3

[0057] Example 3 Compound Con increases intracellular accumulation of the substrate chemotherapeutic drug DOX in ABCB1 or ABCG2 overexpressing cells

[0058] 3.1 Materials

[0059] Human oral cancer cell KB and its ABCB1-overexpressing cell line KBv200, human chronic myeloid leukemia cell line K562 and its ABCB1-overexpressing cell line K562 / adr, human breast cancer cell line MCF-7 and its ABCB1-overexpressing cell line MCF- 7 / adr, human colon cancer cell line S1 and its ABCG2 overexpressing cell line S1-M1-80.

[0060] 3.2 Methods

[0061] Sensitive cell lines KB, K562, MCF-7, S1 in logarithmic growth phase and corresponding drug-resistant cell lines KBv200, K562 / adr, MCF-7 / adr, S1-M1-80 (600,000 / well) were inoculated into Six-well plate; 0 and 1 / 4 IC were added after culturing for 24 hours. 10 , 1 / 2IC 10 , IC 10 Different final concentrations of Con or 10 μM VPR, 2.5 μM Ko134 culture medium; after incubation at 37°C for 3 h, doxorubicin (10 μM) was added to incubate for...

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Abstract

The invention relates to the application of a macrocyclic lactone compound in reversing multi-drug resistance of tumors and enhancing anti-tumor curative effect. The compound can inhibit the activity of ABC transporter and increase the concentration of chemotherapeutic drugs which are substrates of ABC transporter in tumor cells. Reverse tumor multidrug resistance, enhance the curative effect of antibiotic tumor chemotherapeutic drugs, plant-derived tumor chemotherapeutic drugs and small molecule tyrosine kinase inhibitors and other ABC transporter substrate chemotherapeutic drugs, and combine with anti-tumor drugs to enhance the curative effect effect. The effective dose of the compound is used in combination with an effective dose of an antineoplastic drug, including being mixed with an effective dose of an antineoplastic drug to prepare a pharmaceutically acceptable compound preparation, which is used for leukemia, lymphoma, gastric cancer, colon cancer, liver cancer, pancreatic cancer, etc. Cancer, breast cancer, nasopharyngeal cancer, cervical cancer, melanoma, multiple myeloma, sarcoma, including tumor treatment.

Description

technical field [0001] The invention relates to the application of a macrolide compound in enhancing tumor chemotherapy and anti-tumor metastasis, and belongs to the technical field of new drug uses. Background technique [0002] The macrolide compound represented by formula (I), the molecular formula is C 28 H 38 N 2 O 6 , the English name is Conglebatin (this application is referred to as Con) [0003] [0004] It was reported in 1979 that Conglebatin is a compound produced by Streptomyces conglobatus ATCC 31005. It has no antifungal, antibacterial, antiprotozoal, and antitumor activities. It is a low toxicity drug. It is administered at 1g / Kg in mice, and no toxicity is found. Action [J Antibiotics, 1979, 32(9):874-877.]. In recent years, it has been reported that this compound has an anti-tumor effect of inhibiting the function of heat shock 90 protein [Mol Cancer, 13 (2014) 150.], but there is no literature report on the application described in this patent. ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K45/06A61K31/422A61K31/475A61P35/00A61P35/02
CPCA61K45/06A61K31/422A61K31/475A61P35/00A61P35/02A61K2300/00
Inventor 许建华张志强马春玲李鹏叶胜难吴敏
Owner FUJIAN MEDICAL UNIV
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