title: Selumetinib, an Oral Anti-Neoplastic Drug, May Attenuate Cardiac Hypertrophy via Targeting the ERK Pathway.
abstract: OBJECTIVE
  Although 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.
  
  
  RESULTS
  In 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.
  
  
  CONCLUSIONS
  Selumetinib, 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.
authors.affiliation: Department of Cardiology, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Cardiology, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
authors.forename: Zhongxiu
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Cardiology, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Rehabilitation, Community Health Center of Shuangnan Wuhou District, Chengdu, Sichuan, China.
authors.forename: Fangbo
authors.initials: F
authors.lastname: Luo
authors.affiliation: Department of Biochemistry and Molecular Biology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Lihong
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Nuclear Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
authors.forename: Huawei
authors.initials: H
authors.lastname: Cai
authors.affiliation: Department of Cardiology, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
authors.forename: Yajiao
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Cardiology, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
authors.forename: Guiying
authors.initials: G
authors.lastname: You
authors.affiliation: Key Laboratory of Transplant Engineering and Immunology, West China Hospital of Sichuan University, High-tech Zone, Chengdu, Sichuan, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Long
authors.affiliation: Key Laboratory of Transplant Engineering and Immunology, West China Hospital of Sichuan University, High-tech Zone, Chengdu, Sichuan, China.
authors.forename: Shengfu
authors.initials: S
authors.lastname: Li
authors.affiliation: King's College London British Heart Foundation Centre of Research Excellence, Cardiovascular Division, London, United Kingdom.
authors.forename: Qiuping
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
authors.forename: Li
authors.initials: L
authors.lastname: Rao
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use*; D001011:Aorta / Q000187:drug effects / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D006332:Cardiomegaly / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D003251:Constriction, Pathologic; D004195:Disease Models, Animal; D004562:Electrocardiography; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D013312:Stress, Physiological / Q000187:drug effects; D013550:Swimming
chemical_list: C517975:AZD 6244; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D005419:Flavonoids; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one