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首页> 外文期刊>Biochemical Pharmacology >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
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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

机译：在A549细胞中克服紫杉醇抗性：靶向P-GP转运蛋白，AKT / ERK途径和细胞色素P450酶CYP1B1的综合策略（4-羟基胺）

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摘要

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.
机译：紫杉醇的化疗被广泛用作非小细胞肺癌（NSCLC）的一线治疗，然而，随后的紫杉醇抗性发展是一个主要的关注和挑战，导致肿瘤复发和预后差。鉴于紫杉醇抗性的复杂性，我们进一步阐述了其机制，并证明CYP1B1与紫杉醇A549 /紫杉醇细胞中的紫杉醇反应相关。与其父母A549对应物相比，A549 /紫杉醇呈现了更高水平的CYP1B1，其通过增加的芳基烃受体（AHR）表达可能由于长期紫杉醇暴露而平行，从而允许随后的CYP1B1上调。通过TMS抑制CYP1B1 [（e）-2,3'，4,5'-四乙氧基苯乙烯]，特定的CYP1B1抑制剂，显着提高了A549 /紫杉醇至紫杉醇的敏感性。此外，具有人重组CYP1B1的紫杉醇预孵育不影响A549细胞中的药物毒性，这妨碍由于直接灭活紫杉醇而归因于CYP1B1的药物阻力。实际上，CYP1B1负责生物转化的雌激素（E2）进入致癌物质代谢物，其抑制紫杉醇诱导的微管稳定，从而损害治疗效果。值得注意的是，我们的数据揭示了4-羟基二氧化酶（下摆）的有效的CYP1B1抑制功效，如分子对接模拟和EROD测定所反映的，这使得下摆突破e2和CYP1B1之间的恶性循环的优点，不仅有利于克服紫杉醇抵抗力，还通过e2诱导的致癌和肿瘤进展提供长期益处。除了CYP1B1抑制作用外，HEM均显着抑制P-GP活性和表达，耐药性的常用特征，以及有助于细胞增殖，迁移和耐药性的显着灭活的AKT / ERK途径。因此，下摆可以通过综合靶向三次被视为耐药机制的武器来克服紫杉醇抵抗力。此外，下摆在A549和A549 /紫杉肠细胞中，肿瘤刺激的细胞迁移，肿瘤患者死亡率的主要原因，以及对A549 /紫杉醇细胞的选择性损伤而不是正常的肺细胞，支持下摆是一个克服A549细胞克服紫杉醇抗性的承诺剂。

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  • 来源
    《Biochemical Pharmacology》 |2020年第1期|共13页
  • 作者

    Lin Hao; Hu Baichun; He Xiaomei; Mao Jianping; Wang Ying; Wang Jian; Zhang Tingting; Zheng Jiang; Peng Ying; Zhang Fengjiao;

  • 作者单位

    Shenyang Pharmaceut Univ Wuya Coll Innovat Shenyang 110016 Liaoning Peoples R China;

    Shenyang Pharmaceut Univ Minist Educ Key Lab Struct Based Drug Design &

    Discovery Shenyang;

    Shenyang Pharmaceut Univ Wuya Coll Innovat Shenyang 110016 Liaoning Peoples R China;

    Shenyang Pharmaceut Univ Wuya Coll Innovat Shenyang 110016 Liaoning Peoples R China;

    Shenyang Pharmaceut Univ Wuya Coll Innovat Shenyang 110016 Liaoning Peoples R China;

    Shenyang Pharmaceut Univ Minist Educ Key Lab Struct Based Drug Design &

    Discovery Shenyang;

    Shenyang Pharmaceut Univ Wuya Coll Innovat Shenyang 110016 Liaoning Peoples R China;

    Shenyang Pharmaceut Univ Wuya Coll Innovat Shenyang 110016 Liaoning Peoples R China;

    Shenyang Pharmaceut Univ Wuya Coll Innovat Shenyang 110016 Liaoning Peoples R China;

    Shenyang Pharmaceut Univ Wuya Coll Innovat Shenyang 110016 Liaoning Peoples R China;

  • 收录信息
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药理学;
  • 关键词

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

    机译：紫杉醇抵抗;CYP 1B1;P-GP;AKT / ERK;A549;

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