Imbalances in the expression/activity of Bcl-2 family members are believed to play a critical role in malignant transformation, particularly in the case of hematopoietic malignancies. For example, increased expression of Bcl-2 represents a cardinal feature of several B-cell neoplasms, and very likely contributes to chemoresistance. In view of these considerations, attempts to develop inhibitors of anti-apoptotic family members as potential therapeutic agents has recently become the subject of intense interest. In this paper, one such agent, ABT-737, was developed through NMR-based screening and structure-based design, and docks to the hydrophobic groove of the anti-apoptotic proteins Bcl-2 and Bcl-xL, thereby disrupting their function. In preclinical studies, ABT-737 has displayed impressive in vitro and in vivo activity against multiple human tumor cell lines, including those of hematopoietic origin. One theoretical barrier to the effectiveness of ABT-737 stems from its failure to bind to and inhibit Mcl-1, a protein known to be play a critical role in the survival of malignant hematopoietic cells. In this context, several groups have recently reported that first, Mcl-1 expression does in fact represent a critical determinant of ABT-737 activity, and second, multiple interventions that reduce Mcl-1 expression by disparate means dramatically increase the sensitivity of malignant cells, including leukemia cells, to this novel agent1-5 . Such interventions include the use of CDK inhibitors such as roscovitine, which act as transcriptional repressors and downregulate expression of short-lived proteins such as Mcl-1, or alternatively, inhibitors of MEK1/2 (mitogen-activated protein kinase kinase 1/2), which promote Mcl-1 degradation. Interestingly, the simultaneous administration of pharmacologic Bcl-2/Bcl-xL antagonists like ABT-737 and agents that downregulate Mcl-1 expression in essence recapitulates the pro-death actions of more physiologic inhibitors of Bcl-2/Bcl-xL (i.e., Bad) and Mcl-1 (i.e., Noxa). This phenomenon may reflect coordination between Bcl-xL and Mcl-1 in tethering/inactivating the multi-domain pro-apoptotic protein Bak, which cooperates with Bax to trigger mitochondrial injury and apoptosis.
In Brief
The significance of these findings is that, just as the combination of multiple conventional cytotoxic agents has proven active in the clinic, the rational combination of novel, targeted agents may be similarly effective. This could be particularly pertinent in the case of agents which specifically target separate but interrelated arms of the apoptotic machinery. With the possible exception of diseases such as CML, which are characterized by a pronounced dependency upon a critical oncoprotein (i.e., Bcr/Abl), redundancy of tumor cell survival pathways make it unlikely that single interventions employing targeted agents will prove sufficient. The findings described above raise the possibility that the rational targeting of multiple arms of the apoptotic machinery, an approach that offers the prospect of restoring the physiologic death process in leukemic and other neoplastic cells, may be eminently feasible.
References
Competing Interests
Dr. Grant indicated no relevant conflicts of interest.
