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Application of macrolide compound in reversing tumor multidrug resistance and enhancing anti-tumor curative effect

A technology of macrocyclic lactones and compounds, applied in the field of new drug applications, can solve the problems of anti-tumor drugs, such as unsatisfactory effect on tumor metastasis and drug resistance, complex mechanism of tumor drug resistance, etc., to achieve the effect of inhibiting activity and enhancing curative effect

Active Publication Date: 2019-11-22
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 macrolide compound in reversing tumor multidrug resistance and enhancing anti-tumor curative effect
  • Application of macrolide compound in reversing tumor multidrug resistance and enhancing anti-tumor curative effect
  • Application of macrolide compound in reversing tumor multidrug resistance and enhancing anti-tumor curative effect

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Example 1 Compound Con enhances the in vitro anti-tumor effect of ABCB1 or ABCG2 substrate chemotherapeutics 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 MCF-7 / adr, human colon cancer cell line S1 and its ABCG2 overexpression cell line S1-M1-80, human non-small cell lung cancer cell line H460 and its ABCG2 overexpression cell line H460 / MX20, human embryonic kidney cancer The cell line HEK293 and its transfected empty vector cell line HEK293 / pcDNA3.1, ABCB1 stably transfected cell line HEK293 / ABCB1, ABCG2 stably transfected cell line HEK293 / ABCG2-R2. KBv200 cells were added to the culture system with a final concentration of 0.2mg / L of vincristine, K562 / adr, MCF-7 / adr cells were...

Embodiment 2

[0045] Example 2 Compound Con enhances the in vivo anti-tumor effect of substrate chemotherapeutics on ABCB1-mediated drug-resistant cells

[0046] 2.1 Materials

[0047] Human oral epithelial cancer vincristine-resistant cell KBv200, BALB / C-nu nude mice aged 5-6 weeks, SPF-free, male, purchased from Shanghai Slack Laboratory Animal Co., Ltd., production license License number: SCXK (Shanghai) 2012-0002; license number for laboratory animal breeding facilities: SYXK (Min 2016-0007).

[0048] 2.2 Method

[0049] 2.2.1 Establishment of KBv200 transplanted tumor model in nude mice

[0050] Collect 1×10 KBv200 cells in logarithmic growth phase 8 / mL, 3 nude mice were taken as breeding mice, and 0.2mL of cell suspension was injected into each nude mouse subcutaneously in the right forelimb. After the tumor is formed, modeling is performed, and the modeling process is performed in a sterile operating table. Before modeling, the nude mice were anesthetized by intraperitoneal injection of 40...

Embodiment 3

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

[0058] 3.1 Materials

[0059] Human oral cancer cell line 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 overexpression cell line S1-M1-80.

[0060] 3.2 Method

[0061] Take the sensitive cell lines KB, K562, MCF-7, and S1 in the logarithmic growth phase and the corresponding resistant cell lines KBv200, K562 / adr, MCF-7 / adr, S1-M1-80 (600,000 / well) to inoculate Six-well plate; after 24 hours of culture, add 0 and 1 / 4 IC 10 , 1 / 2IC 10 , IC 10 Different final concentrations of Con or 10μM VPR, 2.5μM Ko134 culture medium; after incubating at 37°C for 3h, add doxorubicin (10μM) and incubate for 3h, use the well w...

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Abstract

The invention relates to an application of a macrolide compound in reversing tumor multidrug resistance and enhancing an anti-tumor curative effect. The compound has the functions of inhibiting ABC transport protein activity, improving the concentration of a substrate chemotherapeutic drug of the ABC transport protein in tumor cells, reversing tumor multidrug resistance, and enhancing curative effects of the ABC transport protein substrate chemotherapeutic drugs such as antibiotic tumor chemotherapeutic drugs, plant-derived tumor chemotherapeutic drugs and small-molecular tyrosine kinase inhibitors, and has an effect of enhancing curative effects when being combined with antitumor drugs. Effective dose of the compound is combined with effective dose of an anti-tumor drug for application, apharmaceutically acceptable compound preparation is prepared by mixing with an effective dose of the antitumor drug, and is used for treating tumors including leukemia, lymphoma, gastric cancer, colon cancer, liver cancer, pancreatic cancer, breast cancer, nasopharyngeal carcinoma, cervical carcinoma, melanoma, multiple myeloma, and sarcoma.

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 uses of drugs. 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 (referred to as Con for this application) [0003] [0004] It was reported in 1979 that Conglebatin is a compound produced by Streptomyces conglobatus ATCC 31005. It has no anti-fungal, anti-bacterial, antiprotozoal, or anti-tumor activity. It is a low-toxicity drug. It is administered at 1g / Kg for mice, and no toxicity is found. Role [J Antibiotics,1979,32(9):874-877.]. In recent years, it has been reported that the compound has an anti-tumor effect that inhibits 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. [0005] Malignan...

Claims

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Application Information

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Patent Type & Authority Applications(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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