TY - JOUR T1 - Identification of chemosensitivity nodes for vinblastine through small interfering RNA high- throughput screens. JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.111.184879 SP - jpet.111.184879 AU - Carolyn A. Kitchens AU - Peter R. McDonald AU - Tong Ying Shun AU - Ian F. Pollack AU - John S. Lazo Y1 - 2011/01/01 UR - http://jpet.aspetjournals.org/content/early/2011/08/31/jpet.111.184879.abstract N2 - Discovering chemosensitivity pathways or nodes is an attractive strategy for formulating new drug combinations for cancer. Microtubules are among the most successful anticancer drugs targets. Therefore, we implemented a small interfering RNA (siRNA) synthetic lethal screen targeting 5,520 unique druggable genes to identify novel chemosensitivity nodes for vinblastine, a clinically used microtubule destabilizing agent. We transiently transfected human glioblastoma cells with siRNAs for 48 h and then treated cells with a sub-lethal concentration of vinblastine. Forty-eight h later, we analyzed cell viability and, using a series of statistical methods, identified 65 gene products that, when suppressed, sensitized glioblastoma cells to vinblastine. After completion of the secondary assays, we focused on one siRNA, BCL-xL, because of its role in the intrinsic apoptosis signaling pathway, as well as the availability of pharmacological inhibitors. We found nontoxic concentrations of ABT-263, an inhibitor of the BCL-2 family members (BCL-2, BCL-xL, and BCL-w), sensitized glioblastoma and non-small-cell lung cancer cells to vinblastine and induced apoptosis through the intrinsic cell death pathway. These results illustrate the usefulness of unbiased siRNA screens as a method for identifying potential novel anticancer therapeutic combinations. ER -