p53-Independent induction of apoptosis in human melanoma cells by a bcl-2/bcl-xL bispecific antisense oligonucleotide.

Mutations in the p53 tumor suppressor gene are implicated in defective apoptotic response of tumors to genotoxic damage and, thus, are major determinants of resistance to a variety of anticancer agents. Because even melanomas harboring wild-type (wt) p53 show an abnormal response to radiation and p53 mutations occur late during melanoma progression, we investigated whether the effect of the bcl-2/bcl-xL bispecific antisense oligonucleotide 4625 is dependent on the p53 status in human C8161 melanoma cells. Upon treatment with oligonucleotide 4625, p53-mut C8161 cells showed earlier DNA damage, which occurred concomitantly with the reduction of bcl-2 and bcl-xL expression and the increase in the expression of proapoptotic bax. Loss of cell viability, bcl-2 down-regulation, and poly(ADP-ribose) polymerase cleavage, indicative of apoptosis, also occurred in wt p53 C8161 cells on treatment with oligonucleotide 4625. These effects, however, were mediated by strong induction of p53 without changes in p21 WAF1 expression in wt p53 cells, whereas a 70% decrease in p21 WAF1 expression was observed in mut p53 cells. In contrast to many other anticancer agents to which the apoptotic response is decreased because of p53 mutations, our data suggest that the bcl-2/bcl-xL bispecific antisense oligonucleotide 4625 effectively induces p53-independent apoptosis in human C8161 melanoma cells.