Mitochondria are primary targets in apoptosis induced by the mixed phosphine gold species chlorotriphenylphosphine-1,3-bis(diphenylphosphino)propanegold(I) in melanoma cell lines.
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.
Caruso
Francesco
F
Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche (CNR), Piazzale Aldo Moro 5, 00185 Rome, Italy. francesco.caruso@icb.cnr.it
Villa
Raffaella
R
Rossi
Miriam
M
Pettinari
Claudio
C
Paduano
Francesco
F
Pennati
Marzia
M
Daidone
Maria Grazia
MG
Zaffaroni
Nadia
N
D000970:Antineoplastic Agents / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects*; D050607:Organogold Compounds / Q000494:pharmacology*
D000970:Antineoplastic Agents; D050607:Organogold Compounds; C474152:chlorotriphenylphosphine-1,3-bis(diphenylphosphino)propanegold(I); D053148:Caspase 3; D053453:Caspase 9