increased cytotoxicity of cisplatin in sk-mel 28 melanoma cells upon down-regulation of melanoma inhibitor of apoptosis protein

background: malignant melanoma is a highly metastatic cutaneous cancer and typically refractory to chemotherapy. deregulated apoptosis has been identified as a major cause of cancer drug resistance, and upregulated expression of the inhibitor of apoptosis protein melanom, an inhibitor of apoptosis (ml-iap) is frequent in melanoma. methods: based on the conclusion that ml-iap expression contributes to a malignant phenotype, we down-regulated the ml-iap mrna using sequence optimized antisense oligonucleotides. results: as measured by real-time pcr, oligonucleotides m706 and m711 inhibited ml-iap mrna expression by 47% and 52%, respectively in the highly metastatic and drug resistant sk-mel28 cell line. oligonucleotide m706, which was previously evaluated in g361 cells as the most efficient inhibitor of ml-iap expression, was chosen to compare cell viability and drug sensitivity of these two melanoma cell lines with different p53 functionality. protein expression was reduced by oligonucleotide m706 to 49% of the normal level and resulted in a dose-dependent specific reduction of cell viability with a maximum of 39% at 600 nm. typical morphological changes showed that loss of viability was mainly due to cell death. in combination experiments, the use of oligonucleotide m706 resulted in a two-fold increase of cisplatin cytotoxicity at different concentrations of oligonucleotide and cisplatin (p<0.05). this is in line with our previous findings in g361 melanoma cell line, in which oligonucleotide m706 caused a 3-fold increase in cisplatin cytotoxicity. conclusion: our data suggest the use of ml-iap antisense oligonucleotides to overcome drug resistance in metastatic melanoma, in spite of its p53 status.