Bcl-2-targeted cancer therapeutics

The antiapoptotic members of the Bcl-2 family of proteins play multiple roles in cancer. These membrane-integrated proteins inhibit the pro-apoptotic activity of oncogenes during oncogenesis, support the survival of established cancer cells, and increase resistance to chemotherapy. Hence, strategies aimed at inhibiting the expression or activity of Bcl-2 proteins are predicted to have therapeutic value. Several antisense oligonucleotides (AO), capable of reducing expression of either Bcl-2 or Bcl-X-L, were shown to induce apoptosis in cancer cells, to inhibit tumour growth in certain mouse tumour models, and to sensitise cancer cells to chemotherapy. One such AO, oblimersen, is presently being evaluated in combination with standard therapy in patients with advanced cancers, including chronic lymphocytic leukaemia and multiple myeloma. Bcl-2 proteins are thought to inhibit apoptosis by interacting with the pro-apoptotic proteins Bax and Bak, and preventing their activation. Small molecules capable of inhibiting this interaction have been discovered and shown to induce apoptosis in cancer cells. Gossypol and chelerythrine are two such molecules that inhibit tumour growth in mouse tumour models. This review summarises the evidence supporting the role of Bcl-2 proteins in cancer and then examines patented therapeutic strategies that target Bcl-2 protein expression or activities.