The BCL-2 protein family, BH3-mimetics and cancer therapy

Abstract

Escape from apoptosis is a key attribute of tumour cells and facilitates chemo-resistance. The 'BCL-2-regulated' or 'intrinsic' apoptotic pathway integrates stress and survival signalling to govern whether a cancer cell will live or die. Indeed, many pro-apoptotic members of the BCL-2 family have demonstrated tumour-suppression activity in mouse models of cancer and are lost or repressed in certain human cancers. Conversely, overexpression of pro-survival BCL-2 family members promotes tumorigenesis in humans and in mouse models. Many of the drugs currently used in the clinic mediate their therapeutic effects (at least in part) through the activation of the BCL-2-regulated apoptotic pathway. However, initiators of this apoptotic pathway, such as p53, are mutated, lost or silenced in many human cancers rendering them refractory to treatment. To counter such resistance mechanisms, a novel class of therapeutics, 'BH3-mimetics', has been developed. These drugs directly activate apoptosis by binding and inhibiting select antiapoptotic BCL-2 family members and thereby bypass the requirement for upstream initiators, such as p53. In this review, we discuss the role of the BCL-2 protein family in the development and treatment of cancer, with an emphasis on mechanistic studies using well-established mouse models of cancer, before describing the development and already recognised potential of the BH3-mimetic compounds.

Figure 1

The BCL-2 family members interact to regulate initiation of apoptosis. In healthy cells, the BCL-2-like pro-survival proteins safeguard mitochondrial outer membrane integrity and cell survival by preventing the activation of BAX and BAK. Under conditions of stress, the BH3-only proteins are activated transcriptionally and/or posttranscriptionally to induce apoptosis by releasing BAX/BAK from inhibition by the BCL-2-like proteins or in the case of certain BH3-only proteins (notably BIM, tBID, PUMA) by activating BAX/BAK through direct binding. Once activated, BAX/BAK cause mitochondrial outer membrane permeabilisation (MOMP) with consequent release of apoptogenic molecules (e.g., cytochrome c, SMAC/DIABLO) that cause activation of the caspase cascade that culminates in cellular demolition

Figure 2

Many anticancer agents mediate tumour cell killing though activation of the BCL-2-regulated apoptotic pathway. BH3-only proteins are activated transcriptionally and/or posttranscriptionally in a cytotoxic stimulus-specific manner by many anticancer agents, often with 2–3 members cooperating to induce apoptosis. BH3-mimetic compounds bind directly to and block the BCL-2 pro-survival proteins and thereby elicit apoptosis even in cells lacking upstream activators of BH3-only proteins, such as the tumour-suppressor p53, which is critical for transcriptional induction of Puma and Noxa