Enhancement of drug-induced apoptosis by anti sense oligodeoxynucleotides targeted against Mdm2 and p21(WAF1/CIP1)

The p53 tumor suppressor gene plays an important role in DNA damage-induced apoptosis and, in general, inactivation of p53 contributes to pool respons e to chemotherapy. Apoptotic activity of p53 may be negatively modulated by expression of its downstream mediators, including Mdm2 and p21(WAF1/CIP1). Consequently, these cellular pathways Mdm2 and p21 also represent potentia l targets for cancer therapy. This study investigated the effect of antisen se oligodeoxynucleotides (ODNs), targeted against Mdm2 and p21 on drug-medi ated cell killing. Exposure of U2-OS osteosarcoma cells to DNA damaging age nts, cisplatin or mitomycin C, caused up regulated expression of Mdm2 and p 21 Transient transfection of cells with antisense ODNs to Mdm2 mRNA inhibit ed Mdm2 protein expression and markedly enhanced apoptotic cell death induc ed by these drugs. Moreover, when p21(WAF1/CIP1) expression was blacked by antisense transfection, drug-mediated cell killing was further accelerated. These results suggest that the inhanced expression of Mdm2 and p21(WAF1/CI P1) may inhibit p53-mediated apoptosis and I ender p21 cells resistant to t he effects of DNA damaging agents. Consequently, antisense ODNs targeted ag ainst Mdm2 and p21(WAF1/CIP1) could be employed in a potential therapeutic strategy sensitizing armor cells to cel tain antineoplastic agents.