Targeting Melanoma via Metal-Based Stress
Patrick J. Farmer, Daniel F. Brayton, Christina Moore, Donny Williams, Babbak Shahandeh, Dazhi Cen, Frank Louis Meyskens · ACS symposium series · 2005
Melanoma have an unusual susceptibility to certain lipophilic metal complexes, which is likely due to the pro oxidant effect of metal ions on their endogenous catecholic pigment, melanin. We have investigated the speciation, metal-binding affinity and redox reactivity of the polymeric pigment using synthetic melanins derived from dihydroxyindole, DHI. The binding of certain metal ions to DHI-melanin enhances redox cycling in air and the generation of reactive oxygen species. Our hypothesis is that the toxicity of metal ions to melanoma is via this pro-oxidant reactivity of the pigment. A screening methodology utilizing DHI-melanin reactivity has been developed to identify new candidates for melanoma chemotherapy. Lipophilic metallodithiocarbamate complexes also display selective toxicity against melanoma in culture, which is increased under high O 2 concentrations. Disulfiram, a dithiocarbamate disulfide, has strong activity which is shown to be Cu-dependent. The ability of dithiocarbamates to promote metal uptake and mobility within organisms is discussed.