Pharmacological Inhibition of the Bcl-2 Family of Apoptosis Regulators as Cancer Therapy

Abstract

Conventional chemotherapy for cancer utilizes cytotoxic agents which elicit their therapeutic effect in part through the induction of apoptosis. In contrast, drugs which have been developed more recently and which are referred to as "targeted therapy" may exhibit less unwanted toxicity but in some cases these drugs are cytostatic. The recent development of drugs which target the apoptotic machinery offers a means to combine these two approaches. The intrinsic apoptotic pathway is controlled by the balance between anti-apoptotic proteins belonging to the Bcl-2 family and pro-apoptotic proteins bearing a single BH3 domain. Anti-apoptotic Bcl-2 family members are able to sequester the pro-apoptotic proteins by binding their BH3 domain. Compounds which inhibit this interaction are expected to promote apoptosis by preventing sequestration of the pro-apoptotic protein. Recently, a number of drugs have been developed which accomplish this, eg ABT-737, and some of these are progressing to clinical trials in oncology. These drugs may induce apoptosis on their own or synergize with existing chemotherapy. For example, ABT-737 is able to induce apoptosis when used as a single agent to treat leukemic and lung cancer cells and has also been shown to synergize with conventional chemotherapeutic agents in several cancer types. The spectrum of Bcl-2 family members expressed in a tumor cell, and the specificity of the inhibitor for these different anti-apoptotic proteins, helps determine whether Bcl-2 antagonists induce apoptosis when used as single agents. The ability of cytotoxic drugs to alter the expression of pro- and anti-apoptotic proteins is likely to help determine whether Bcl-2 antagonists synergize with cytotoxic therapy. Finally, as we begin to understand the pathways that regulate the expression of pro- and anti-apoptotic pathways, several new therapeutic strategies can be envisioned.