c-MET酪氨酸激酶抑制剂通过靶向ABCG2转运蛋白逆转乳腺癌细胞中的多药耐药性。

c-MET tyrosine kinase inhibitors reverse multidrug resistance in breast cancer cells by targeting ABCG2 transporter.

作者信息

Nazari Somayeh, Mosaffa Fatemeh, Poustforoosh Alireza, Saso Luciano, Firuzi Omidreza, Moosavi Fatemeh

机构信息

Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.

Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.

出版信息

J Pharm Pharmacol. 2025 May 2;77(5):685-697. doi: 10.1093/jpp/rgaf008.

DOI:10.1093/jpp/rgaf008

PMID:40053482

Abstract

BACKGROUND

Overcoming multidrug resistance (MDR), which is often caused by the overexpression of ATP binding cassette (ABC) transporters in cancer cells remains a major challenge for cancer treatment. Receptor tyrosine kinase inhibitors have demonstrated potential in reversing MDR. This study aimed to investigate the effects of c-MET RTKIs on the reversal of MDR induced by ABCG2 in breast cancer cells.

METHODS

MTT assay was employed to assess antiproliferative activity of c-MET inhibitors, including cabozantinib, crizotinib, and PHA665752. The accumulation of the fluorescent probe mitoxantrone was evaluated by flow cytometry. The drug-drug interaction in combination treatments was analyzed using CalcuSyn software.

RESULTS

The combination of cabozantinib, crizotinib, and PHA665752 with mitoxantrone resulted in synergistic effects in MDR cells. This was demonstrated by the mean CI values of 0.32 ± 0.07, 0.53 ± 0.05, and 0.59 ± 0.03, respectively. In the same cells, c-MET inhibitors enhanced the accumulation of mitoxantrone, with accumulation ratios ranging from 1.6 to 3.8, while no change was found in parental MCF-7 cells. Computational analysis revealed that the drug-binding region of ABCG2 transporters could be a viable target for these compounds.

CONCLUSION

c-MET inhibitors hold potential as effective agents for reversing MDR in ABCG2-medicated drug-resistant cancer cells.

摘要

背景

克服多药耐药性（MDR）是癌症治疗的一项重大挑战，多药耐药性通常由癌细胞中ATP结合盒（ABC）转运蛋白的过表达引起。受体酪氨酸激酶抑制剂已显示出逆转多药耐药性的潜力。本研究旨在探讨c-MET受体酪氨酸激酶抑制剂对乳腺癌细胞中ABCG2诱导的多药耐药性逆转的影响。

方法

采用MTT法评估c-MET抑制剂（包括卡博替尼、克唑替尼和PHA665752）的抗增殖活性。通过流式细胞术评估荧光探针米托蒽醌的蓄积情况。使用CalcuSyn软件分析联合治疗中的药物相互作用。

结果

卡博替尼、克唑替尼和PHA665752与米托蒽醌联合使用对多药耐药细胞产生协同作用。平均CI值分别为0.32±0.07、0.53±0.05和0.59±0.03，证明了这一点。在相同细胞中，c-MET抑制剂增强了米托蒽醌的蓄积，蓄积率为1.6至3.8，而亲本MCF-7细胞未发现变化。计算分析表明，ABCG2转运蛋白的药物结合区域可能是这些化合物的可行靶点。