These data are consistent with ABT 737 causing increased caspase

These data are consistent with ABT 737 causing increased caspase 9 activation by caspase 8. This, in turn, results in more caspase 3 7 activation and then retrograde activation of caspase 8 by caspase 3 7. Treatment of a panel of breast cancer cell lines with 5 uM ABT 737 by using sub IC50 concentra tions of TRAIL, enhanced TRAIL induced toxicity buy inhibitor in all of the breast cancer subtypes tested. The combined treatment of TRAIL plus ABT 737 inhibited viability more than TRAIL alone or ABT 737 alone in all cells tested. The tox icity of the combined treatment was greater than the sum of the toxicities for the individual treatments for all cell lines, except for MB157. Again the high sensi tivity to TRAIL alone in this cell line probably accounts for the failure of ABT 737 to enhance significantly the toxicity by Inhibitors,Modulators,Libraries this analysis.

Discussion TRAIL is a promising cancer therapeutic agent showing efficacy against tumor cells Inhibitors,Modulators,Libraries and not affecting normal cells. However, in vitro experiments have found that many cancer cell lines Inhibitors,Modulators,Libraries are resistant to TRAIL. The underlying determinants of TRAIL sensitivity are not clearly understood. Investigations into Inhibitors,Modulators,Libraries the mechanisms in cells that regulate sensitivity to TRAIL have implicated sev eral pathways and factors. Regulation of the TRAIL recep tors at the level of expression, localization to the cell surface, and O glycosylation of the receptor proteins par tially, but not fully, correlate with sensitivity. TRAIL resistance is also associated with elevated ex pression of antiapoptotic factors like c FLIP, IAP fam ily proteins, and BCL 2.

In ongoing clinical trials, responses to TRAIL have been rare, especially in solid tumors. Therefore we need to identify proteins that regulate the TRAIL path way, as they could potentially serve as predictive bio markers of TRAIL sensitivity and or provide additional targets for enhancing the efficacy of TRAIL. Inhibitors,Modulators,Libraries To this end, we performed primary siRNA screens of the human kinome, phosphatome, and some additional genes to identify regulators of TRAIL induced apoptosis in the MB231 breast cancer cell line. We identified 150 genes as putative negative regulators of TRAIL induced caspase 3 7 activation. For this study, we adapted commercially available assays of caspase 8, caspase 3 7, and cell viability for high throughput siRNA screens, including the identification of highly sensitive biologically relevant controls.

Good positive Ganetespib structure correlation was found between those siRNAs that enhanced TRAIL induced caspase 3 7 and those that enhanced TRAIL induced caspase 8 activation. Good inverse correlation was seen between the TRAIL induced enhancement of caspase activation and the viabil ity of TRAIL treated cells. Thus, the three assays together strengthen the likelihood that the identified genes are regulators of the TRAIL pathway.

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