Discovery of Coumarin as Microtubule Affinity-Regulating Kinase 4 Inhibitor That Sensitize Hepatocellular Carcinoma to Paclitaxel.

Xianyan Shen,Wenchen Pu,Shunli Wan,Yong Peng,Xuesha Liu,Huaiyu He,Xin Fan,Chun Wang,Rong Wei

doi:10.3389/fchem.2019.00366

Abstract

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 50 as a novel MARK4 inhibitor. Biological evaluation indicated compound 50 directly interacted with MARK4 and inhibited its activity in vitro, suppressed cell viability and induced apoptosis of HCC cells in a MARK4-dependent manner. Importantly, compound 50 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.

Highlights

Hepatocellular carcinoma (HCC) is one of the leading causes of human death worldwide (Bray et al, 2018)
We demonstrated that microtubule affinity-regulating kinase 4 (MARK4) inhibitor has the ability to enhance the sensitivity of paclitaxel toward HCC cells (Figure 5), providing a novel insight for HCC treatment and enlarging the potential application for paclitaxel
We revealed that coumarin-based compound 50 targted MARK4 kinase to sentisize HCC cells to paclitaxel treatment, enlarging the therapeutical potential of coumarins in human cancers

Summary

Introduction

Hepatocellular carcinoma (HCC) is one of the leading causes of human death worldwide (Bray et al, 2018). Several therapies have been developed, such as sorafenib, the first-line targeted drug for advanced HCC, their efficacies are not satisfactory, rendering a poor prognosis for HCC patients (Galle, 2008; Llovet et al, 2008). Novel therapy is urgently needed for HCC treatment. Paclitaxel, firstly isolated in 1971 from the Pacific yew, is the Food and Drug Administration (FDA)-approved therapy exhibiting promising efficacy against diverse solid tumors including breast, ovarian, lung, cervical and pancreatic cancers (Wang et al, 2011; Pignata et al, 2015; Schmid et al, 2018). The data of clinical trial reveals that the anticancer effect of paclitaxel toward HCC patients is limited (Chao et al, 1998; Kavallaris, 2010). Our recent work indicates the depletion of microRNA-122

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Conclusion