Model for the regulation of the mitochondrial pathway of apoptosis by Bcl-2-family members.

1. In the absence of apoptotic stimuli, Bak molecules reside in the outer mitochondrial membrane but do not oligomerize to form pores; Mcl-1 may associate with Bak to block Bak self-association.

2. Apoptosis-inducing signals promote the movement of BH3-only proteins to the outer mitochondrial membrane (OMM), where some BH3-only family members (e.g., Bid, Bim) transiently associate with Bak or Bax to induce a conformational change resulting in formation of homo-oligomers and induction of apoptosis.

3. Antiapoptotic proteins such as Mcl-1 and Bcl-XL (or Bcl-2, not shown) may be overexpressed in multiple myeloma (MM) cells and sequester BH3-only proteins and prevent their interaction with Bak or Bax, thus overcoming cell death signals. Inhibition of expression of antiapoptotic proteins in MM cells could overcome this tumor survival mechanism.

4. Antiapoptotic effects of Mcl-1 and Bcl-XL can be overcome by excess BH3-only proteins.

5. Resistance to apoptosis may be reversed by the development of low molecular weight, cell-permeable drugs (D) that bind to the hydrophobic BH1-3 pocket of Mcl-1 and/or Bcl-XL, thus preventing the sequestration of BH3-only proteins. The latter are then free to interact with Bak and Bax with the subsequent formation of pores and induction of apoptosis. Efforts are in progress to identify novel compounds that specifically target Mcl-1 (D1) or Bcl-XL (D2).