TY - JOUR
T1 - Peculiar mechanistic and structural features of the carboplatin-cytochrome c system revealed by ESI-MS analysis
AU - Gabbiani, Chiara
AU - Casini, Angela
AU - Mastrobuoni, Guido
AU - Kirshenbaum, Noam
AU - Moshel, Ofra
AU - Pieraccini, Giuseppe
AU - Moneti, Gloriano
AU - Messori, Luigi
AU - Gibson, Dan
PY - 2008/6
Y1 - 2008/6
N2 - 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.
AB - 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.
KW - Carboplatin
KW - Cytochrome c
KW - Electrospray ionisation mass spectrometry
KW - Mechanism of action
KW - Metallodrugs
UR - http://www.scopus.com/inward/record.url?scp=44549084093&partnerID=8YFLogxK
U2 - 10.1007/s00775-008-0361-z
DO - 10.1007/s00775-008-0361-z
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
C2 - 18350322
AN - SCOPUS:44549084093
SN - 0949-8257
VL - 13
SP - 755
EP - 764
JO - Journal of Biological Inorganic Chemistry
JF - Journal of Biological Inorganic Chemistry
IS - 5
ER -