Targeting Mcl-1 and other Bcl-2 family member proteins in cancer therapy

Abstract

Regulation of both the extrinsic and the mitochondria-dependent intrinsic apoptotic pathways plays a key role in the development of the hematopoietic system, for sustaining cell survival during generation of various cell types, in eliminating cells with dual identities such as CD4/CD8 double-positive cells (Hettmann, Didonato, Karin, & Leiden, 1999; Ogasawara, Suda, & Nagata, 1995), for sustaining cells during the rapid clonal expansion phase (Schirmer, Vallejo, Weyand, & Gronzy, 1998), as well as eliminating cells during the contraction phase (Yajima et al., 2006). The anti-apoptotic protein Mcl-1 is necessary for sustaining hematopoietic stem cells (HPS) (Akashi et al., 2003; Akashi, Traver, Miyamoto, & Weissman, 2000). The anti-apoptotic factors Mcl-1, Bcl-2, and Bcl-xL were also found to be over-expressed in acute myeloid leukemia (AML) (Kaufmann et al., 2016) and acute lymphocytic leukemia (ALL) (Findley, Gu, Yeager, & Zhou, 1997), suggesting that dis-regulated apoptotic processes could be a factor in the instigation of leukemia and/or its relapse. Molecules targeting these proteins were used as single agents to treat leukemia. However, by using a set of recently developed specific molecule inhibitors targeting anti-apoptotic proteins, distinct roles are being discovered for these anti-apoptotic proteins during hematopoietic and tumor development. Furthermore, using these inhibitors in proper combinations can effectively induce apoptosis in various solid tumors, even though each agent on its own cannot induce apoptosis in them. These new findings suggest that inhibiting anti-apoptotic elements can induce apoptosis without external stimuli in most cells, but it comes with a risk that some combinations could also trigger apoptosis in healthy cells. One way to address the safety issue is by limiting exposure to all the agents to only cancer cells, thus making the combination safe and effective. In this article, we review this rapidly developing idea in cancer research.

Keywords: ABT-263; Apoptosis; Bcl-2; Bcl-xL; Mcl-1; S63845.