Ruthenium(ii) complex containing cinnamic acid derivative inhibits cell cycle progression at G0/G1 and induces apoptosis in melanoma cells

Abstract

Melanoma is a highly aggressive skin cancer with a limited targeted therapy arsenal. Ruthenium-based complexes have shown interesting pro-apoptotic effects on malignant tumor cell lines. In this study three ruthenium(II) complexes containing cinnamic acid derivatives as ligands were synthesized and characterized and their cytotoxic profile was evaluated on four melanoma cell lines (HT-144, SK-MEL-147, CHL-1, and WM1366). All complexes significantly reduced cell viability in a concentration-dependent manner. However, complex (2) bearing trans-4-(trifluoromethyl)cinnamic acid as the ligand was the most promising compound. We demonstrated that complex (2) inhibits cell cycle progression at the G1 phase and induces apoptosis in the CHL-1 cell line. Our data showed that cell cycle arrest at G1/S transition was, at least in part, due to reduction of ERK activation, CDKN1A (p21) upregulation and CCNE2 (cyclin E2) downregulation. Moreover, pro-apoptotic activity of complex (2) was ascribed to its ability to modulate BAX and Bcl-2 expression profiles leading to an increase in the BAX/Bcl-2 ratio. We also demonstrated that complex (2) affects the actin cytoskeleton organization pattern and inhibits the migration of CHL-1. Taken together, the data indicate the promising antitumor potential of complex (2) against melanoma cells and support further in vivo studies.