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  2. Overcoming Taxol-resistance in A549 cells: A comprehensive strategy of targeting P-gp transporter, AKT/ERK pathways, and cytochrome P450 enzyme CYP1B1 by 4-hydroxyemodin

Overcoming Taxol-resistance in A549 cells: A comprehensive strategy of targeting P-gp transporter, AKT/ERK pathways, and cytochrome P450 enzyme CYP1B1 by 4-hydroxyemodin

  • Biochem Pharmacol. 2020 Jan;171:113733. doi: 10.1016/j.bcp.2019.113733.
Hao Lin 1 Baichun Hu 2 Xiaomei He 1 Jianping Mao 1 Ying Wang 1 Jian Wang 2 Tingting Zhang 1 Jiang Zheng 1 Ying Peng 1 Fengjiao Zhang 3
Affiliations

Affiliations

  • 1 Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China.
  • 2 Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China.
  • 3 Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China. Electronic address: zhangfengjiao@syphu.edu.cn.
Abstract

Taxol-based chemotherapy is widely used as the first-line treatment for non-small cell lung Cancer (NSCLC), however, the subsequent development of taxol-resistance is a major concern and challenge, resulting in tumor relapse and poor prognosis. Given the complex nature of taxol-resistance, we further delved into its mechanisms and demonstrated that CYP1B1 was associated to taxol response in taxol-resistant A549/Taxol cells. Compared to its parent A549 counterpart, A549/Taxol presented much higher level of CYP1B1, which was paralleled by increased Aryl Hydrocarbon Receptor (AhR) expressions likely due to the long term taxol exposure and thereby allowed a subsequent up-regulation of CYP1B1. Inhibition of CYP1B1 by TMS [(E)-2,3',4,5'-tetramethoxystilbene], the specific CYP1B1 inhibitor, remarkably enhanced the sensitivity of A549/Taxol to taxol. Moreover, pre-incubation of taxol with human recombinant CYP1B1 did not affect drug toxicity in A549 cells, precluding the possibility of drug resistance ascribed to CYP1B1 due to directly inactivating taxol. Indeed, CYP1B1 is responsible for bio-transforming estrogen (E2) into the carcinogenetic metabolite that would inhibit microtubule stabilization induced by taxol and thereby compromising treatment efficacy. Remarkably, our data revealed potent CYP1B1 inhibition efficacy of 4-hydroxyemodin (HEM) as reflected by both molecular docking simulations and EROD assay, which posed HEM the advantage of breaking the vicious circle between E2 and CYP1B1, not only favoring to overcome taxol-resistance, but also offering long term benefit via circumventing carcinogenesis and tumor progression induced by E2. In addition to CYP1B1 inhibition, HEM notably inhibited P-gp activity and expression, a common feature of drug resistance, as well as significantly inactivated Akt/ERK pathways that contributed to the cell proliferation, migration, and drug resistance. Thus, HEM may act in concert to overcome taxol-resistance through comprehensive targeting three considered arms of drug-resistance mechanisms. Moreover, HEM profoundly resisted E2-stimulated cell migration in both A549 and A549/Taxol cells, a primary reason for tumor patients' mortality, as well as inflicted selective injury to A549/Taxol cells rather than normal lung cells, supporting HEM to be a promising agent for overcoming taxol-resistance in A549 cells.

Keywords

A549; AKT/ERK; CYP 1B1; P-gp; Taxol-resistance.

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