Novel 2-phenyloxypyrimidine derivative induces apoptosis and autophagy via inhibiting PI3K pathway and activating MAPK/ERK signaling in hepatocellular carcinoma cells

Jing Wang,Peng Sun,Shuzhen Wang,Hequan Yao,Yijun Chen

doi:10.1038/s41598-018-29199-8

Abstract

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality globally. Because most patients are diagnosed at advanced stages of the disease, multi-targeted tyrosine kinase inhibitor sorafenib is the only available drug to show limited effectiveness. Novel and effective therapies are unmet medical need for advanced HCC patients. Given that the aberrant expression and activity of platelet-derived growth factor receptor α (PDGFRα) are closely associated with the pathogenesis of HCC, here we present the discovery and identification of a novel PDGFRα inhibitor, N-(3-((4-(benzofuran-2-yl)pyrimidin-2-yl)oxy)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide (E5) after comparison of different derivatives. We found that E5 inhibited proliferation and induced apoptosis in HCC cells. Since the pan-caspase inhibitor Z-VAD-FMK partially rescued HCC cells from E5-reduced cell viability, autophagic cell death triggered by E5 was subsequently investigated. E5 could induce the conversion of LC3-I to LC3-II, increase the expression of Atg5 and restore the autophagy flux blocked by chloroquine. Meanwhile, E5 was able to downregulate the PDGFRα/PI3K/AKT/mTOR pathway and to activate MAPK/ERK signaling pathway. Taken together, in addition to the possibility of E5 as a valuable drug candidate, the present study further supports the notion that targeted inhibition of PDGFRα is a promising therapeutic strategy for HCC.

Highlights

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality globally
In a previous attempt to compare different chemotypes, we found that substitution of the 2phenylaminopyrimidine core of imatinib with 2-phenyloxypyrimidine abolished the inhibition to most kinases, while preserved the inhibitory activity to PDGFRα12, suggesting that 2-phenyloxypyrimidine core can be explored as a scaffold for the design of generation of selective platelet-derived growth factor receptor α (PDGFRα) inhibitors
Since it has been widely recognized that the over-expression of PDGFRα promotes tumorigenesis most frequently through phosphatidylinositol 3-kinase (PI3K) signaling in human malignancies[17,18], we investigated the effects of E5 on PI3K/AKT/mammalian target of rapamycin (mTOR) cascade

Summary

Introduction

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality globally. Because most patients are diagnosed at advanced stages of the disease, multi-targeted tyrosine kinase inhibitor sorafenib is the only available drug to show limited effectiveness. There are several different types of treatments currently available for HCC patients, the molecular targeted agent sorafenib, a broad-spectrum tyrosine kinase inhibitor (TKI), is the only US Food and Drug Administration (FDA)-approved drug to show significant survival advantages in late-stage HCC patients[3]. Extensive exploration of other novel and effective molecular targeted therapies are urgently needed to enhance current therapy and to provide more treatment options for advanced HCC patients. High expression of PDGFRβ has been reported in HCC patients, growing evidence has indicated that the aberrant expression and activity of PDGFRα are more closely associated with the pathogenesis of HCC, indicating that the inhibition of PDGFRα may represent a new potential therapeutic strategy for HCC8,9. In a previous attempt to compare different chemotypes, we found that substitution of the 2phenylaminopyrimidine core of imatinib with 2-phenyloxypyrimidine abolished the inhibition to most kinases, while preserved the inhibitory activity to PDGFRα12, suggesting that 2-phenyloxypyrimidine core can be explored as a scaffold for the design of generation of selective PDGFRα inhibitors

Methods

Results

Conclusion