Abstract
Abstract Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis that may have promise as an anticancer agent due to its selectivity toward tumor cells. However, resistance to TRAIL occurs frequently and is primarily due to defects in apoptosis signaling or activation of survival pathways. Sunitinib is an inhibitor of multiple receptor tyrosine kinases that promote cell survival and drug resistance. We hypothesized that disrupting pro-survival signaling cascades with suntinib would circumvent this mechanism of resistance and strongly enhance TRAIL-mediated apoptosis. We tested this hypothesis by investigating whether inhibition of survival signaling pathways with sunitinib could augment the anticancer activity of TRAIL in preclinical models of colon cancer. Sunitinib significantly enhanced the anticancer activity of TRAIL in a panel of colon cancer cell lines as evidenced by increased caspase cleavage and DNA fragmentation. The TRAIL/sunitinib combination also promoted enhanced JNK activation and stimulated a decrease in the expression of XIAP, c-IAP2 and Bcl-xL, which correlated with apoptosis. siRNA-mediated knockdown of JNK reduced TRAIL/sunitinib-mediated apoptosis indicating that it is an important mediator of efficacy of this combination. We further investigated this combination regimen in HCT116 and HCT15 xenograft models treated with vehicle, TRAIL, sunitinib, or the combination. The TRAIL/sunitinib combination was very well tolerated and significantly reduced tumor burden in both models compared to either single agent treatment. The reduction in tumor volume correlated with increased apoptosis as measured by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and was associated with decreases in XIAP, c-IAP2 and Bcl-xL expression. Our collective results suggest that sunitinib enhances TRAIL-mediated apoptosis by increasing JNK activation and downregulating multiple anti-apoptotic proteins. These findings are the first report of the therapeutic potential of the combination of sunitinib and TRAIL in preclinical models of colon cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 669.
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