The mechanism of calicheamicin γ1-mediated cytotoxicity was studied in human promyelocytic HL-60 leukemic cells. Calicheamicin γ1 caused an increase in poly(ADP-ribose) polymerase activity in HL-60 cells parallel to cell death. This effect of the drug correlated with a decrease in intracellular NAD+ level. 3-Aminobenzamide, an inhibitor of poly(ADP-ribosylation), prevented the calicheamicin γ1-triggered cytotoxicity in a dose-dependent manner. Simultaneous with the reversal of cytotoxicity, the addition of 3-aminobenzamide to drug-treated cells also inhibited the increase in poly(ADP-ribosylation) and the reduction in cellular NAD+ content. These results indicate that poly(ADP-ribosylation) activation and the subsquent perturbations in NAD+-dependent metabolic reactions are associated with the cytotoxic properties of the antitumor antibiotic calicheamicin γ1.
ASJC Scopus subject areas
- Cancer Research