Selumetinib, an Oral Anti-Neoplastic Drug, May Attenuate Cardiac Hypertrophy via Targeting the ERK Pathway.

Chen Li,Hao Yang,Huawei Cai,Yajiao Li,Shengfu Li,Li Rao,Fangbo Luo,Qiuping Zhang,Dan Long,Lihong Chen,Zhongxiu Chen,Guiying You

doi:10.1371/journal.pone.0159079

Abstract

AimsAlthough extracellular-regulated kinases (ERK) are a well-known central mediator in cardiac hypertrophy, no clinically available ERK antagonist has been tested for preventing cardiac hypertrophy. Selumetinib is a novel oral MEK inhibitor that is currently under Phase II and Phase III clinical investigation for advanced solid tumors. In this study, we investigated whether Selumetinib could inhibit the aberrant ERK activation of the heart in response to stress as well as prevent cardiac hypertrophy.Methods and ResultsIn an in vitro model of PE-induced cardiac hypertrophy, Selumetinib significantly inhibited the ERK activation and prevented enlargement of cardiomyocytes or reactivation of certain fetal genes. In the pathologic cardiac hypertrophy model of ascending aortic constriction, Selumetinib provided significant ERK inhibition in the stressed heart but not in the other organs. This selective ERK inhibition prevented left ventricular (LV) wall thickening, LV mass increase, fetal gene reactivation and cardiac fibrosis. In another distinct physiologic cardiac hypertrophy model of a swimming rat, Selumetinib provided a similar anti-hypertrophy effect, except that no significant fetal gene reactivation or cardiac fibrosis was observed.ConclusionsSelumetinib, a novel oral anti-cancer drug with good safety records in a number of Phase II clinical trials, can inhibit ERK activity in the heart and prevent cardiac hypertrophy. These promising results indicate that Selumetinib could potentially be used to treat cardiac hypertrophy. However, this hypothesis needs to be validated in human clinical trials.

Highlights

Cardiac hypertrophy is an increase in the heart size in response to physiological or pathological stress, such as extensive physical exercise, hypertension, valvular disorder or coronary artery disease[1]
Selumetinib Attenuates Cardiac Hypertrophy promising results indicate that Selumetinib could potentially be used to treat cardiac hypertrophy
We found that a very small dosage of Selumetinib was sufficient to block extracellular-regulated kinases (ERK) activity in tumor cells(Fig 1A)

Summary

Introduction

Cardiac hypertrophy is an increase in the heart size in response to physiological or pathological stress, such as extensive physical exercise, hypertension, valvular disorder or coronary artery disease[1]. Cardiac hypertrophy is mediated by a variety of intracellular signaling cascades[4,5]. Among these prohypertrophic signaling pathways, the extracellular-regulated kinases (ERKs) are a well-known central mediator[6,7]. The ERK pathway is activated in response to every stress- and agonistinduced hypertrophic stimulus examined to date, and blocking the ERK signaling pathway prevents against cardiac hypertrophy in vitro and in vivo[8,9,10,11]. The ERK inhibitors or genetic modification approaches used in these cell and animal studies have been far from providing a clinically available treatment option for cardiac hypertrophy

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