April 15, 2005

Targeting Melanoma via Metal-Induced Oxidative Stress: a coordination chemistry approach

Dr. Patrick Farmer
Department of Chemistry
University of California, Irvine

Abstract: Melanoma cancers are particularly drug-resistant and deadly; they also have an unusual susceptibility towards metal ions, which may be due to the pro-oxidant reactivity of their endogenous melanin pigments. Melanins are catecholic polymers formed from tyrosine oxidation; the binding of certain metal ions to melanin enhances their reactivity with oxygen, generating cytotoxic superoxide and hydroxyl radicals. We proposed to use this pro-oxidant response to chemically target melanoma, and we have shown that both oxygen and metal ion carriers are selectively toxic to this form of cancer. We have identified certain lipophilic dithiocarbamates that induce metal uptake into melanoma cells in culture, resulting in oxidative stress and a dramatic apoptotic response. Investigations into this apoptotic response have lead to identification of other metallocomplexes with high anti-melanoma activity.


Some recent papers ordered by relevance:

"Disulfiram causes intracellular Cu uptake and induces apoptosis in human melanoma cells" Cen, D.; Brayton, D.; Shahandeh, B.; Meyskens, F.L.; Farmer, P.J. J. Med. Chem. 2004, 47, 6914-6920.

"Melanin as a target for melanoma chemotherapy: pro-oxidant effect of oxygen and metals on melanoma viability." Farmer, P.J.; Gidanian, S.; Shahandeh, B.; Di Bilio, A.J.; Tohidian, N.; Meyskens, F.L.; Pigment Cell. Res. 2003, 16, 273-279.

"Metal Binding by Melanins: Studies of Colloidal DHI-Melanin, and its Complexation by Cu(II), and Zn(II) Ions " Szpoganicz, B.; Gidanian, S.;  Kong, P.; Farmer, P.J J. Inorg. Biochem. 2002, 89, 45-53.

"Etiologic Pathogenesis of Melanoma: A Unifying Hypothesis for the Missing Attributable Risk" Meyskens, F.L.; Farmer, P.J.; Anton-Culver, H. Clin. Canc.  Res.  2004, 10, 2581-2583.

"The Effect of Stacking and Redox State on Optical Absorption Spectra of Melanins- a comparison of theoretical and experimental results." Stark, K.B.; Gallas, J.M.; Zajac G.W.;  Golab, J.T.; Gidanian, S.; McIntire, T.; Farmer, P.J. J. Phys. Chem. B. 2005 109, 1970-1977.