Shen Xianyan, Liu Xuesha, Wan Shunli, Fan Xin, He Huaiyu, Wei Rong, Pu Wenchen, Peng Yong, Wang Chun
Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China.
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital and College of Life Sciences, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China.
Front Chem. 2019 May 24;7:366. doi: 10.3389/fchem.2019.00366. eCollection 2019.
Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide. Nowadays, pharmacological therapy for HCC is in urgent needs. Paclitaxel is an effective drug against diverse solid tumors, but commonly resisted in HCC patients. We recently have disclosed that microtubule affinity-regulating kinase 4 (MARK4) increases the microtubule dynamics and confers paclitaxel resistance in HCC, suggesting MARK4 as an attractive target to overcome paclitaxel resistance. Herein, we synthesized and identified coumarin derivatives as a novel MARK4 inhibitor. Biological evaluation indicated compound directly interacted with MARK4 and inhibited its activity , suppressed cell viability and induced apoptosis of HCC cells in a MARK4-dependent manner. Importantly, compound significantly increased the drug response of paclitaxel treatment to HCC cells, providing a promise strategy to HCC treatment and broadening the application of paclitaxel in cancer therapy.
肝细胞癌（HCC）是全球最常见的癌症之一。如今，HCC的药物治疗迫在眉睫。紫杉醇是一种对多种实体瘤有效的药物，但在HCC患者中普遍耐药。我们最近发现，微管亲和力调节激酶4（MARK4）增加微管动力学并赋予HCC对紫杉醇的抗性，这表明MARK4是克服紫杉醇抗性的一个有吸引力的靶点。在此，我们合成并鉴定了香豆素衍生物作为一种新型MARK4抑制剂。生物学评价表明，化合物直接与MARK4相互作用并抑制其活性，以MARK4依赖的方式抑制细胞活力并诱导HCC细胞凋亡。重要的是，化合物显著增加了紫杉醇治疗对HCC细胞的药物反应，为HCC治疗提供了一种有前景的策略，并拓宽了紫杉醇在癌症治疗中的应用。
