Abstract:
Resistance to apoptosis is a prominent feature of melanoma. Pharmacological concentration of
arsenic in combination with a widely known oxidant, menadione was explored in this study to synergistically
sensitize malignant melanoma cells to apoptosis. The molecular mechanism of apoptosis and the signalingpathways involved were thoroughly investigated. Materials methods and results Menadione synergized NaAsO2 to significantly increase ROS generation and facilitate the major apoptotic signaling events: alteration of mitochondrial membrane potential, cytochrome c release and anti-apoptotic protein Bcl-2 down-regulation and subsequent activation of caspase-9 and caspase-3 followed by poly-ADP-ribose polymerase-1 cleavage. Antioxidant N-acetyl-L-cysteine antagonized these events. Investigation
of the signaling-pathway revealed significant suppression of AP-1 activity but not NF-jB upon NaAsO2 and menadione application. An increase in p38 phosphorylation and p53 protein expression did also dictate the apoptotic response. Suppression of p38 activation with SB203580 and inhibition of p53 expression by siRNA attenuated apoptosis.