K Connolly, R Mitter, M Muir, D Jodrell, S Guichard
Cancer Chemother Pharmacol
PURPOSE: To develop a model of X-linked inhibitor of apoptosis (XIAP) down regulation in colorectal cancer cell lines. This may be used to determine whether combination strategies have clinical potential. METHODS: A series of clones were developed using short hairpin RNA (shRNA) against XIAP stably expressed in HCT116 cells. XIAP mRNA and protein levels were established by RT-PCR and Immunoblot, respectively. GeneChip microarrays confirmed XIAP knockdown and absence of compensation by other IAP members. RESULTS: Four XIAP knockdown cell lines show 82-93% reduction in XIAP mRNA and 67-89% reduction in protein when compared to four luciferase control cell lines. XIAP knockdown sensitises cells to rhTRAIL by a factor of 3, to paclitaxel and docetaxel by a factor of >2 and, to a lesser extent, radiotherapy (20% enhancement). CONCLUSIONS: Clinical trials with XIAP antisense continue, and these data suggest combination studies with agents such as rhTRAIL and taxanes should be undertaken.