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 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.

Metformin and propranolol combination prevents cancer progression and metastasis in different breast cancer models

“…It was previously shown that Prop reduces intracellular calcium levels, Bax-mediated cytochrome C release and inhibits protein kinase C (PKC) activity in a β-adrenoreceptor independent manner [19–21], and it induces cell cycle arrest and apoptosis via Akt/MAPK pathway in melanoma cells [22]. Many studies in humans have demonstrated its efficacy for the treatment of infantile haemangioma.…”

Propranolol Suppresses Cobalt Chloride-Induced Hypoxic Proliferation in Human Umbilical Vein Endothelial Cells in vitro

“…Therefore, propranolol, a commercial nonselective β-AR blocker, is now recommended as an important drug in first-line treatment against IH [25,26]. Although propranolol shows remarkable response rates, there are still some major adverse effects, such as changes in sleep, acrocyanosis, hypotension, and hypoglycemia, which raise serious clinical concerns [27,28]. IH pathogenesis, especially the mechanism associated with hypoxic proliferation, awaits urgent clarification.…”

β‐Adrenoceptors as drug targets in melanoma: novel preclinical evidence for a role of β3‐adrenoceptors

“…Among the signalling pathways involved in melanoma growth, NA acting on β 1 ‐ and β 2 ‐adrenoceptors activates the Gs/cAMP/PKA pathway thus leading to increased expression of VEGF and inflammatory cytokines (Yang et al ., ; Deng et al ., ). In addition, in human melanoma cells, propranolol has been found to inhibit the Akt and MAPK pathways thus promoting apoptosis and decreasing cell viability (Zhou et al ., ). Moreover, in mouse melanoma cells, propranolol prevents the activation of different pathways including the activation of Akt, STAT3 and iNOS (Dal Monte et al ., ).…”

“…In melanoma cells, propranolol prevents the NA‐induced cell proliferation, likely through the activation of apoptotic processes (Dal Monte et al ., ; Moretti et al ., ; Calvani et al ., ; Wrobel and Le Gal, ; Zhou et al ., ). In mouse models of melanoma, propranolol delays primary tumour growth and metastasis development, thus reducing melanoma progression and improving the survival rate (Hasegawa and Saiki, ; Glasner et al ., ; Barbieri et al ., ; Wrobel and Le Gal, ; Wrobel et al ., ; Zhou et al ., ; Kuang et al ., ; Maccari et al ., ).…”