TP53 alteration determines the combinational cytotoxic effect of doxorubicin and an antioxidant NAC.

Abstract

The anticancer effect of doxorubicin is closely related to the generation of reactive oxygen species. On the contrary, doxorubicin-induced reactive oxygen species induces heart failure, a critical side effect of doxorubicin. Antioxidant supplementation has been proposed to reduce the side effects. However, the use of antioxidants may hamper the anticancer effect of doxorubicin. In this study, doxorubicin-induced reactive oxygen species was shown to differentially affect cancer cells based on their TP53 genetic status; doxorubicin-induced apoptosis was attenuated by an antioxidant, N-acetylcysteine, in TP53 wild cells; however, N-acetylcysteine caused a synergistic increase in the apoptosis rate in TP53-altered cells. N-acetylcysteine prevented phosphorylation of P53 protein that had been induced by doxorubicin. However, N-acetylcysteine increased the cleavage of poly (ADP-ribose) polymerase in the presence of doxorubicin. Synergy score of 26 patient-derived cells were evaluated after the combination treatment of doxorubicin and N-acetylcysteine. The synergy score was significantly higher in TP53-altered group compared with those in TP53 wild group. In conclusion, TP53 genetic alteration is a critical factor that determines the use of antioxidant supplements during doxorubicin treatment.