Copper and two molecules of diethyl dithiocarbamate [DEDTC] form the Cu[DEDTC](2) complex, which shows cytotoxicity against
melanoma and
carcinoma cells, making it a potentially useful anti-
cancer agent. The differential response to Cu[DEDTC](2) in susceptible human SKBR3
carcinoma and C8161
melanoma cell variants of moderate and high resistance to this organometallic complex was evaluated in this study. Both cell lines underwent apoptosis-associated PARP cleavage, changes in expression of nuclear NFkB p65, p21WAF1 and
cyclin A, with loss of clonogenicity in response to this agent. However, a threefold greater concentration [IC(50) 0.6 microM DEDTC: 0.3 microM Cu] was required to kill moderately resistant C8161
melanoma compared to highly susceptible SKBR3 cells. Decreased susceptibility to Cu[DEDTC](2) in C8161
melanoma correlated with greater levels of
glutathione peroxidase and
catalase, and a fourfold lower requirement for N-acetyl
cysteine (1mM) to overcome toxicity. Whereas
melanoma cells selected for resistance to [0.8 microM DEDTC: 0.4 microM Cu] showed persistent
catalase and GPx activity,
melanoma cells with moderate susceptibility showed decreased
catalase and Gpx when responding to treatment. Cytotoxic response in moderately susceptible C8161
melanoma cells involved an early accumulation of pro-apoptotic Bax in the G2 cell cycle phase, followed by an increased ratio of pro-apoptotic Bak to anti-apoptotic Mcl-1 in mitochondria. Our data suggests that Cu[DEDTC](2) toxicity is mediated through an increase in pro-apoptotic Bak/Bax via disruption of the
peroxide and
thiol metabolism.