1. Academic Validation
  2. YAN, a novel microtubule inhibitor, inhibits P-gp and MRP1 function and induces mitotic slippage followed by apoptosis in multidrug-resistant A549/Taxol cells

YAN, a novel microtubule inhibitor, inhibits P-gp and MRP1 function and induces mitotic slippage followed by apoptosis in multidrug-resistant A549/Taxol cells

  • Toxicol In Vitro. 2020 Dec;69:104971. doi: 10.1016/j.tiv.2020.104971.
Minghuan Gao 1 Tong Liu 1 Jingnan Li 1 Qi Guan 2 Haoran Wang 2 Shuqi Yan 2 Zengqiang Li 1 Daiying Zuo 3 Weige Zhang 2 Yingliang Wu 1
Affiliations

Affiliations

  • 1 Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
  • 2 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
  • 3 Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China. Electronic address: zuodaiying@163.com.
Abstract

Lung Cancer is the most common cause of cancer-related death worldwide. The occurrence of multidrug resistance (MDR) affects the therapeutic efficacy of chemotherapeutics. Therefore, to develop new anticarcinogen which can overcome MDR is urgent. Here, the novel microtubule inhibitor 5-(4-ethoxyphenyl)-1-(3,4,5-trimethoxyphenyl)-1H-1,2,4-triazol-3-amine (YAN) exhibited strong cytotoxicity towards A549 and MDR-phenotype A549/Taxol cells. We demonstrated that YAN was a poor substrate of P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1) which were over-expressed in A549/Taxol cells, and YAN inhibited their expression and function. Moreover, YAN arrested cells at mitosis phase by inhibiting microtubule polymerization. Further, YAN induced caspase-dependent Apoptosis in A549 cells via mitochondria-mediated intrinsic pathway. In contrast, the multinucleation of A549/Taxol cells after YAN-treatment indicated the occurrence of mitotic catastrophe, and the subsequent Apoptosis was mediated by apoptosis-inducing factor (AIF) nuclear translocation instead of p53- and caspase-dependent manner. Moreover, the inhibitory effect of YAN on PI3K/Akt activity was involved in the regulation of P-gp, MRP1 and AIF in A549/Taxol cells. Taken together, our finding indicates that YAN is a novel microtubule inhibitor and overcomes MDR by suppressing P-gp and MRP1 function and inducing cell death independent of p53 and Caspase in A549/Taxol cells. Therefore, YAN possesses great potential for future development into an effective anticarcinogen especially for drug-resistant Cancer.

Keywords

Apoptosis; Cell cycle arrest; Multidrug resistance; Multidrug resistance-associated protein 1; P-glycoprotein.

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