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Aurora kinase B inhibitors induce apoptosis secondary to polyploidization and have entered clinical trials as an emerging class of neocytotoxic chemotherapeutics. We demonstrate here that polyploidization neutralizes Mcl-1 function, rendering cancer cells exquisitely dependent on BcI-XL/-2. This 'addiction' can be exploited therapeutically by combining aurora kinase inhibitors and the orally bioavailable BH3 mimetic, ABT-263, which inhibits BcI-XL, Bcl-2, and Bcl-w. The combination of ABT-263 with aurora B inhibitors produces a synergistic loss of viability in a range of cell lines of divergent tumor origin and exhibits more sustained tumor growth inhibition in vivo compared with aurora B inhibitor monotherapy. These data demonstrate that BcI-XL/-2 is necessary to support viability during polyploidization in a variety of tumor models and represents a druggable molecular vulnerability with potential therapeutic utility. apoptosis | aurora kinase | Bcl-XL | polyploidy doi/10.1073/pnas.0913615107

The effectiveness of IFN-[alpha]2b for human multiple myeloma has been variable. TRAIL has been proposed to mediate IFN-[alpha]2b apoptosis in myeloma. In this study we assessed the effects of IFN-[alpha]2b [...]

The phospholipase A(sub 2) enzymes are important components of the cellular machinery that responds to inflammatory stimuli and maintains cell homeostasis by membrane remodelling. Their role as the rate-limiting step in the production of pro-inflammatory lipid mediators makes these enzymes an important therapeutic target for the treatment of inflammatory disorders. Keith Glaser and colleagues explain how the two major groups of phospholipase A(sub 2), the secretory and cytosolic forms, are very different both structurally and enzymatically. Understanding the relative contributions of these different forms of phospholipase A(sub 2) to physiological and pathological conditions requires greater insight into their cellular regulation and the development of selective inhibitors.