Apoptosis, the major physiological cell death program that removes unwanted or damaged cells, is controlled by the opposing factions of the Bcl-2 family of proteins. Bcl-2 and its homologs (Bcl-xL, Bcl-w, Mcl-1 and A1) are anti-apoptotic, while the closely related Bax and Bak are pro-apoptotic. The distantly related BH3-only proteins also promote cell death, by binding to a hydrophobic groove on the pro-survival proteins, preventing their inhibition of Bax and Bak activity. Certain BH3-only proteins can also bind weakly and transiently to Bax and/or Bak, triggering their activation.
Chemical mimetics of BH3-only proteins are an exciting new class of cancer therapeutic. The most promising thus far are ABT-737 and the related orally available compound ABT-263 (navitoclax) developed by Abbott Laboratories. Both ABT-737 and ABT-263 bind with high affinity to Bcl-2, Bcl-xL and Bcl-w. As Bcl-xL is critical for platelet survival, the interaction of ABT-737 or ABT-263 with Bcl-xL causes acute thrombocytopenia, which has proven to be the dose-limiting toxicity. The thrombocytopenia provoked by inhibition of Bcl-xL could be avoided by using a BH3-mimetic that is specific for Bcl-2.
In this study we have investigated the in vivo efficacy of a Bcl-2-specific BH3-mimetic for treating tumours we have shown previously to be responsive to ABT-737: lymphomyeloid progenitor cell lymphomas from Eµ-myc/Eµ-bcl-2 bitransgenic mice. In addition, as these lymphomas have high levels of the BH3-only protein Bim, which is thought to be critical for responsiveness to ABT-737 in CLL, we generated tumours lacking Bim to determine whether it is required for the response of Eµ-myc/Eµ-bcl-2 tumours to BH3-mimetics.