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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

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.

Original languageEnglish
Pages (from-to)755-764
Number of pages10
JournalJournal of Biological Inorganic Chemistry
Volume13
Issue number5
DOIs
StatePublished - Jun 2008

Keywords

  • Carboplatin
  • Cytochrome c
  • Electrospray ionisation mass spectrometry
  • Mechanism of action
  • Metallodrugs

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