Biorelevant reactions of the potential anti-tumor agent vanadocene dichloride.
The interaction of the potential anti-tumor agent vanadocene dichloride ([Cp2VCl2] or VDC) with some relevant bioligands of the cytosol such as proteins (Hb), amino acids (glycine and histidine), NADH derivatives (NADH, NADPH, NAD(+) and NADP(+)), reductants (GSH and ascorbic acid), phosphates (HPO4(2-), P2O7(4-), cAMP, AMP, ADP and ATP) and carboxylate derivatives (lactate) and its uptake by red blood cells were studied. The results indicated that [Cp2VCl2] transforms at physiological pH into [Cp2V(OH)2] and that only HPO4(2-), P2O7(4-), lactate, ATP and ADP form mixed species with the [Cp2V](2+) moiety replacing the two hydroxide ions. EPR and electronic absorption spectroscopy, agarose gel electrophoresis and spin trapping measurements allow excluding any direct interaction and/or intercalation with DNA and the formation of reactive oxygen species (ROS) in Fenton-like reactions. Uptake experiments by erythrocytes suggested that VDC crosses the membrane and enters inside the cells, whereas 'bare' V(IV) transforms into V(IV)O species with loss of the two cyclopentadienyl rings. This transformation in the cellular environment could be related to the mechanism of action of VDC.
Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, UOS di Sassari, Trav. La Crucca 3, I-07040 Sassari, Italy.
Daniele
D
Sanna
Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, UOS di Sassari, Trav. La Crucca 3, I-07040 Sassari, Italy.
Maria
M
Serra
Dipartimento di Chimica e Farmacia, Università di Sassari, Via Vienna 2, I-07100 Sassari, Italy. garribba@uniss.it.
Valeria
V
Ugone
Dipartimento di Scienze Biomediche, Università di Sassari, Via Muroni 25, I-07100 Sassari, Italy.
Laura
L
Manca
Dipartimento di Scienze Biomediche, Università di Sassari, Via Muroni 25, I-07100 Sassari, Italy.
Monica
M
Pirastru
Department of Inorganic and Analytical Chemistry, University of Debrecen, P.O. Box 21, H-4010 Debrecen, Hungary.
Péter
P
Buglyó
Department of Inorganic and Analytical Chemistry, University of Debrecen, P.O. Box 21, H-4010 Debrecen, Hungary.
Linda
L
Bíró
Dipartimento di Chimica e Farmacia, Università di Sassari, Via Vienna 2, I-07100 Sassari, Italy. garribba@uniss.it.
Giovanni
G
Micera
Dipartimento di Chimica e Farmacia, Università di Sassari, Via Vienna 2, I-07100 Sassari, Italy. garribba@uniss.it.
Eugenio
E
Garribba
D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D004247:DNA / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects; D006801:Humans; D008024:Ligands; D017382:Reactive Oxygen Species / Q000378:metabolism; D017968:Vanadium Compounds / Q000378:metabolism / Q000494:pharmacology*
D000970:Antineoplastic Agents; D008024:Ligands; D017382:Reactive Oxygen Species; D017968:Vanadium Compounds; C030754:vanadocene dichloride; D004247:DNA