| 17188248 |
Caruso F, Villa R, Rossi M, Pettinari C, Paduano F, Pennati M, Daidone MG, Zaffaroni N: Mitochondria are primary targets in apoptosis induced by the mixed phosphine gold species chlorotriphenylphosphine-1,3-bis (diphenylphosphino) propanegold (I) in melanoma cell lines. Biochem Pharmacol. 2007 Mar 15;73(6):773-81. Epub 2006 Nov 28.
Based on previous evidence indicating a selective cytotoxic activity of the mixed phosphine gold complex chlorotriphenylphosphine-1,3-bis (diphenylphosphino) propanegold (I) for melanoma cells, we investigated the cellular bases of its antiproliferative effect in a panel of human melanoma cell lines (JR8, SK-Mel-5, Mel-501, 2/60, 2/21 and GRIG). The drug consistently induced a dose-dependent inhibition of cell growth, with IC50 values ranging from 0.8 to 2.3 microM and, when tested under the same experimental conditions, its cytotoxic activity was higher than (from 2- to 5-fold) or comparable to that of cisplatin as a function of cell lines. The ability of the gold complex to activate programmed cell death was assessed in JR8 and 2/60 cells, and a dose-dependent increase in cells with an apoptotic nuclear morphology was observed in both cell lines (up to 40 and 66% of the overall cell population, for JR8 and 2/60 cell lines, respectively). Such an apoptotic response was mediated by a dose-dependent loss of mitochondrial membrane potential, cytochrome c and Smac/DIABLO release from mitochondria into cytosol and enhanced caspase-9 and caspase-3 catalytic activity. A reduced or completely abrogated expression of the anti-apoptotic proteins c-IAP1, XIAP and survivin in drug-treated cells was also observed. Overall, results from the study indicate that chlorotriphenylphosphine-1,3-bis (diphenylphosphino) propanegold (I) markedly inhibits melanoma cell growth by inducing mitochondria-mediated apoptosis and suggest it as a good candidate for additional evaluation as an anticancer agent against melanoma. |
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