Carboplatin (CPT), today the most important platinum(II) anticancer drug, manifests an extreme kinetic inertness, in vitro, at physiological pH; the actual mechanisms for its activation inside cells are still poorly understood. We show here that horse heart cytochrome c reacts with CPT, leading to the formation of stable platinum/protein adducts. The two major CPT-cytochrome c species resulting from the aforementioned reaction were characterised by electrospray ionisation mass spectrometry (ESI-MS). Notably, both these adducts have the ability to react with guanosine 5'-monophosphate (5'-GMP), giving rise to the respective cytochrome c-CPT-5'-GMP ternary complexes. Additional ESI-MS measurements on enzymatically cleaved cytochrome c adducts suggest that protein platination probably occurs at Met65. The mechanistic implications of these findings are discussed.
Peculiar mechanistic and structural features of the carboplatin-cytochrome c system revealed by ESI-MS analysis / Chiara Gabbiani; Angela Casini; Guido Mastrobuoni; Noam Kirshenbaum; Ofra Moshel; Giuseppe Pieraccini; Gloriano Moneti; Luigi Messori; Dan Gibson. - In: JBIC. - ISSN 0949-8257. - STAMPA. - 13:(2008), pp. 755-764.
Peculiar mechanistic and structural features of the carboplatin-cytochrome c system revealed by ESI-MS analysis
PIERACCINI, GIUSEPPE;MONETI, GLORIANO;MESSORI, LUIGI;
2008
Abstract
Carboplatin (CPT), today the most important platinum(II) anticancer drug, manifests an extreme kinetic inertness, in vitro, at physiological pH; the actual mechanisms for its activation inside cells are still poorly understood. We show here that horse heart cytochrome c reacts with CPT, leading to the formation of stable platinum/protein adducts. The two major CPT-cytochrome c species resulting from the aforementioned reaction were characterised by electrospray ionisation mass spectrometry (ESI-MS). Notably, both these adducts have the ability to react with guanosine 5'-monophosphate (5'-GMP), giving rise to the respective cytochrome c-CPT-5'-GMP ternary complexes. Additional ESI-MS measurements on enzymatically cleaved cytochrome c adducts suggest that protein platination probably occurs at Met65. The mechanistic implications of these findings are discussed.File | Dimensione | Formato | |
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