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.
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Abbreviations
- cbdca:
-
1,1-Cyclobutanedicarboxylate
- CPT:
-
Carboplatin
- en:
-
Ethylenediamine
- ESI:
-
Electrospray ionisation
- 5′-GMP:
-
Guanosine 5′-monophosphate
- MS:
-
Mass spectrometry
- TMeAmAc:
-
Tetramethylammonium acetate
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Acknowledgments
The authors gratefully acknowledge support from Ente Cassa di Risparmio di Firenze. A.C. and C.G. wish to thank AIRC for providing them with research fellowships.
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Gabbiani, C., Casini, A., Mastrobuoni, G. et al. Peculiar mechanistic and structural features of the carboplatin–cytochrome c system revealed by ESI-MS analysis. J Biol Inorg Chem 13, 755–764 (2008). https://doi.org/10.1007/s00775-008-0361-z
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DOI: https://doi.org/10.1007/s00775-008-0361-z