Mitochondria are primary targets in apoptosis induced by the mixed phosphine gold species chlorotriphenylphosphine-1,3-bis(diphenylphosphino)propanegold(I) in melanoma cell lines.

Abstract

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.

• Authors: Francesco Caruso, Raffaella Villa, Miriam Rossi, Claudio Pettinari, Francesco Paduano, Marzia Pennati, Maria Grazia Daidone, Nadia Zaffaroni
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 73 Issue 6 Pg. 773-81 (Mar 15 2007) ISSN: 0006-2952 [Print] England
• PMID: 17188248 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Organogold Compounds
• chlorotriphenylphosphine-1,3-bis(diphenylphosphino)propanegold(I)
• Caspase 3
• Caspase 9

Topics

• Antineoplastic Agents (pharmacology)
• Caspase 3 (metabolism)
• Caspase 9 (metabolism)
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Humans
• Melanoma (drug therapy, pathology)
• Mitochondria (drug effects)
• Organogold Compounds (pharmacology)