title: Propranolol induced G0/G1/S phase arrest and apoptosis in melanoma cells via AKT/MAPK pathway.
abstract: 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 mm3vs. 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.
authors: Department of Clinical Pharmacology, XiangYa Hospital, Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China.
authors: Chengfang
authors: C
authors: Zhou
authors: Department of Dermatology, XiangYa Hospital, Central South University, Changsha, China.
authors: Xiang
authors: X
authors: Chen
authors: Department of Dermatology, XiangYa Hospital, Central South University, Changsha, China.
authors: Weiqi
authors: W
authors: Zeng
authors: Department of Dermatology, XiangYa Hospital, Central South University, Changsha, China.
authors: Cong
authors: C
authors: Peng
authors: Department of Orthopedics, Hunan Tumor Hospital, Changsha, China.
authors: Gang
authors: G
authors: Huang
authors: Department of Orthopedics, Hunan Tumor Hospital, Changsha, China.
authors: Xian'an
authors: X
authors: Li
authors: Department of Orthopedics, Hunan Tumor Hospital, Changsha, China.
authors: Zhengxiao
authors: Z
authors: Ouyang
authors: Department of Orthopedics, Hunan Tumor Hospital, Changsha, China.
authors: Yi
authors: Y
authors: Luo
authors: Department of Orthopedics, Hunan Tumor Hospital, Changsha, China.
authors: Xuezheng
authors: X
authors: Xu
authors: Department of Clinical Pharmacology, XiangYa Hospital, Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China.
authors: Biaobo
authors: B
authors: Xu
authors: Department of Clinical Pharmacology, XiangYa Hospital, Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China.
authors: Weili
authors: W
authors: Wang
authors: Department of Clinical Pharmacology, XiangYa Hospital, Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China.
authors: Ruohui
authors: R
authors: He
authors: Department of Dermatology, XiangYa Hospital, Central South University, Changsha, China.
authors: Xu
authors: X
authors: Zhang
authors: Department of Neurosurgery, Xiang-Ya Hospital, Central South University, Changsha, China.
authors: Liyang
authors: L
authors: Zhang
authors: Department of Clinical Pharmacology, XiangYa Hospital, Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China.
authors: Jie
authors: J
authors: Liu
authors: Moffitt Cancer Center, DeBartolo Family Personalized Medicine Institute, Tampa, FL, USA.
authors: Todd C
authors: TC
authors: Knepper
authors: Department of Clinical Pharmacology, XiangYa Hospital, Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China.|Moffitt Cancer Center, DeBartolo Family Personalized Medicine Institute, Tampa, FL, USA.|Department of Dermatology, XiangYa Hospital, Central South University, Changsha, China.
authors: Yijing
authors: Y
authors: He
authors: Department of Clinical Pharmacology, XiangYa Hospital, Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China.|Moffitt Cancer Center, DeBartolo Family Personalized Medicine Institute, Tampa, FL, USA.
authors: Howard L
authors: HL
authors: McLeod
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D011433:Propranolol / Q000494:pharmacology*; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000319:Adrenergic beta-Antagonists; D011433:Propranolol
keywords: AKT pathway; MAPK pathway; apoptosis; melanoma; propranolol