SAT-008 Overcoming BCL-2 Resistance in Glucocorticoid-Treated Tumor Lymphoid Cells

Glucocorticoids are prescribed in many chemotherapy protocols for neoplasms of lymphoid origin based on their ability to inhibit lymphocyte proliferation and promote cell death (apoptosis). Lymphocytes have been shown to be profoundly sensitive to glucocorticoid-induced apoptosis, however glucocorticoid resistance restricts the efficacy of these stress hormones and reduces their clinical value. Bcl-2 is an anti-apoptotic protein that promotes cell survival and resistance to cell death during glucocorticoid therapy. Predictably, Bcl-2, as well as other anti-apoptotic Bcl-2 family members, have been found to be overexpressed in a variety of human cancers, including in over 90% of human follicular lymphomas and 95% of chronic lymphocytic leukemias. Unfortunately, approaches to overcome Bcl-2 resistance in cancer cells including anti-sense oligonucleotides, drugs that inhibit Bcl-2 function, and BH3 mimics have not been effective. We took a unique approach to overcome Bcl-2 resistance in tumor cells expressing this anti-apoptotic protein by first identifying points along glucocorticoid-induced cell death signaling program that are explicitly inhibited by Bcl-2. We then intervened at this stage that bypasses the point of inhibition. Provocatively, drugs such as CCCP and several microbial toxins which disrupt the mitochondrial membrane potential, when used in combination with glucocorticoids overcome the resistance afforded by Bcl-2 and kills the cells. Our data suggests drugs which alter the mitochondrial membrane potential in combination with glucocorticoids provide an effective approach in killing lymphocytic tumor cells expressing Bcl-2. This combination should be considered in accompanying current chemotherapeutic drug combinations to provide additional therapeutic benefit in overcoming Bcl-2 resistant tumors.