Modulation of cisplatinum cytotoxicity by p53: Effect of p53-mediated apoptosis and DNA repair

A stable transfectant (S2SN7) of p53-null SaOS-2 (human osteosarcoma) cells expressing wild-type p53 under the tight control of a tetracycline-respons ive promoter was used to study the functional roles of p53 in cellular resp onse to cisplatinum (CP). When cells were grown in media containing normal concentrations (10%) of serum, induction of p53 by tetracycline withdrawal resulted in an 8-fold decrease in sensitivity to CP. In contrast, when cell s were grown in lower serum (1%) media, induction of p53 led to a 10-fold i ncrease in sensitivity to CP. The p53-mediated sensitivity to CP under lowe r serum conditions was attributed, at least in part, to increased susceptib ility of p53-mediated apoptosis. Under lower serum (0.1-1%) but not normal serum conditions, p53 induction correlated with selective down-regulation o f bcl-2, an inhibitor of apoptosis. In addition, a host-cell reactivation a ssay showed that induction of p53 caused a significant increase in repair o f CP-induced DNA damage under normal serum but not low serum conditions. Th ese data suggest that growth conditions may modulate and possibly reverse p 53-mediated CP sensitivity by altering p53-mediated gene regulation and, as a result, susceptibility to apoptosis. They also suggest that a combined e ffect of p53-mediated apoptosis and DNA repair may be the ultimate determin ant in p53-mediated cellular resistance or sensitivity to chemotherapeutic drugs.