Propranolol induced G0/G1/S phase arrest and apoptosis in melanoma cells via AKT/MAPK pathway
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Chengfang Zhou1, Xiang Chen3, Weiqi Zeng3, Cong Peng3, Gang Huang4, Xian’an Li4, Zhengxiao Ouyang4, Yi Luo4, Xuezheng Xu4, Biaobo Xu1, Weili Wang1, Ruohui He1, Xu Zhang3, Liyang Zhang5, Jie Liu1, Todd C. Knepper2, Yijing He1,2,3, Howard L. McLeod1,2
1Department of Clinical Pharmacology, XiangYa Hospital, Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China
2Moffitt Cancer Center, DeBartolo Family Personalized Medicine Institute, Tampa, FL, USA
3Department of Dermatology, XiangYa Hospital, Central South University, Changsha, China
4Department of Orthopedics, Hunan Tumor Hospital, Changsha, China
5Department of Neurosurgery, Xiang-Ya Hospital, Central South University, Changsha, China
Howard L. McLeod, email: Howard.McLeod@moffitt.org
Yijing He, email: email@example.com
Keywords: melanoma, propranolol, apoptosis, AKT pathway, MAPK pathway
Received: February 15, 2016 Accepted: August 12, 2016 Published: August 25, 2016
Both preclinical and epidemiology studies associate β-adrenoceptors-blockers (β-blockers) with activity against melanoma. However, the underlying mechanism is still unclear, especially in acral melanoma. In this study, we explored the effect of propranolol, a non-selective β-blocker, on the A375 melanoma cell line, two primary acral melanoma cell lines (P-3, P-6) and mice xenografts. Cell viability assay demonstrated that 50μM-400μM of propranolol inhibited viability in a concentration and time dependent manner with an IC50 ranging from 65.33μM to 148.60μM for 24h -72h treatment, but propranolol (less than 200μM) had no effect on HaCaT cell line. Western blots showed 100μM propranolol significantly reduced the expression of Bcl-2 while increasing the expressions of Bax, cytochrome c, cleaved capase-9 and cleaved caspase-3, and down-regulated the levels of p-AKT, p-BRAF, p-MEK1/2 and p-ERK1/2 in melanoma cells, after a 24h incubation. The in vivo data confirmed the isolation results. Mice received daily ip. administration of propranolol at the dose of 2 mg/kg for 3 weeks and the control group was treated with the same volume of saline. The mean tumor volume at day 21 in A375 xenografts was 82.33 ± 3.75mm3vs. 2044.67 ± 54.57mm3 for the propranolol-treated mice and the control group, respectively, and 31.66 ± 4.67 mm3 vs. 1074.67 ± 32.17 mm3 for the P-3 xenografts. Propranolol also reduced Ki67, inhibited phosphorylation of AKT, BRAF, MEK1/2 and ERK1/2 in xenografts. These are the first data to demonstrate that propranolol might inhibit melanoma by activating the intrinsic apoptosis pathway and inactivating the MAPK and AKT pathways.
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