Poly(ADPR)polymerase inhibition and apoptosis induction in cDDP-treated human carcinoma cell lines.
Poly(ADPR)polymerases' (PARPs) inhibitors potentiate the cytotoxic effects of chemotherapeutic agents like alkylating compounds and TOPO I poisons, while their action in combination with cisplatin still needs investigation. In fact, one of the earliest responses to DNA single- or double-strand breaks is the synthesis of poly(ADP-ribose) (PAR) by PARPs; these enzymes are components of DNA repair machineries and substrates of caspases. Cisplatin (cDDP) yields intra- and inter-strand DNA cross-links and several proteins that recognise cDDP-induced DNA damage, such as p53, are also targets of poly(ADP-ribosyl)ation. We compared the effects of treatments with cDDP and the PARPs inhibitor PJ34 in p53 mutated carcinoma cell lines (HeLa, KB, HT29) that exhibited differential sensitivities to the drugs, in terms of cell growth inhibition and onset of apoptosis. In cDDP-resistant HT29 cells we determined: (i) PJ34 potentiation of cDDP-induced cell growth inhibition; (ii) an increment of PARP-1 automodification following cDDP treatment. In cDDP-sensitive HeLa cells, we found that the drug induced apoptotic cell death associated with caspase-dependent PARP-1 proteolysis.
Gambi
Nadia
N
Department of Structural and Functional Biology, University Federico II of Naples, Via Cinthia Monte S. Angelo, 80126 Napoli, Italy.
Tramontano
Filomena
F
Quesada
Piera
P
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001345:Autoradiography; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006801:Humans; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013997:Time Factors
D000970:Antineoplastic Agents; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D002945:Cisplatin