PloS one, 2016-07, Vol.11 (7), p.e0159079
2016
Details
- Autor(en) / Beteiligte
- Titel
- Selumetinib, an Oral Anti-Neoplastic Drug, May Attenuate Cardiac Hypertrophy via Targeting the ERK Pathway
- Ist Teil von
- PloS one, 2016-07, Vol.11 (7), p.e0159079
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2016
- Link zum Volltext
- Quelle
- EZB Electronic Journals Library
- Beschreibungen/Notizen
- 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. 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. 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0159079Titel-ID: cdi_plos_journals_1805755911
- Format
- –
- Schlagworte
- Aberration, Activation, Administration, Oral, Animals, Antimitotic agents, Antineoplastic agents, Antineoplastic Agents - administration & dosage, Antineoplastic Agents - therapeutic use, Aorta, Aorta - drug effects, Aorta - pathology, Apoptosis, Apoptosis - drug effects, Benzimidazoles - administration & dosage, Benzimidazoles - pharmacology, Benzimidazoles - therapeutic use, Biology and Life Sciences, Cancer, Cancer therapies, Cardiology, Cardiomegaly - diagnostic imaging, Cardiomegaly - drug therapy, Cardiomegaly - enzymology, Cardiomegaly - genetics, Cardiomyocytes, Cardiovascular disease, Clinical trials, Constriction, Pathologic, Disease Models, Animal, Drug therapy, Electrocardiography, Enlargement, Enzyme Activation - drug effects, Extracellular signal-regulated kinase, Extracellular signal-regulated kinases, Extracellular Signal-Regulated MAP Kinases - metabolism, Fetuses, Fibrosis, Flavonoids - pharmacology, Gene Expression Regulation - drug effects, Health aspects, Heart, Heart diseases, Heart enlargement, Heart hypertrophy, Hypertension, Hypertrophy, Immunology, Inhibition, Kinases, Laboratories, MAP Kinase Signaling System - drug effects, Medical prognosis, Medical research, Medicine and Health Sciences, Melanoma, Metabolic pathways, Musculoskeletal system, Mutation, Myocytes, Cardiac - drug effects, Myocytes, Cardiac - metabolism, Myocytes, Cardiac - pathology, Organs, Physiological aspects, Physiology, Prevention, Proto-Oncogene Proteins c-akt - metabolism, Rats, Research and Analysis Methods, Risk factors, Rodents, Solid tumors, Stress, Physiological - drug effects, Studies, Swimming, Thickening, Tumors, Ventricle