Mimicking the BH3 domain to kill cancer cells

Abstract

Cancer cells show deviant behavior that induces apoptotic signaling. To survive, cancer cells typically acquire changes enabling evasion of death signals. One way they do this is by increasing the expression of anti-apoptotic BCL-2 proteins. Anti-apoptotic BCL-2 family proteins antagonize death signaling by forming heterodimers with pro-death proteins. Heterodimer formation occurs through binding of the pro-apoptotic protein's BH3 domain into the hydrophobic cleft of anti-apoptotic proteins. The BH3 mimetics are small molecule antagonists of the anti-apoptotic BCL-2 members that function as competitive inhibitors by binding to the hydrophobic cleft. Under certain conditions, antagonism of anti-apoptotic BCL-2 family proteins can unleash pro-death molecules in cancer cells. Thus, the BH3 mimetics are a new class of cancer drugs that specifically target a mechanism of cancer cell survival to selectively kill cancer cells.

Fig 1. The mitochondrial apoptotic pathway

Cellular stress activates both sensitizer and activator BH3-only proteins. The sensitizer BH3-only proteins inhibit the anti-apoptotic BCL-2 family, while the direct activators cause the activation leading to oligomerization and insertion of BAX and BAK into the mitochondrial membrane. Mitochondrial outer membrane permeabilization (MOMP) causes the release of Cytochrome c, which forms a complex with caspase-9, APAF-1 and dATP/dADP triggering downstream apoptotic events.

Fig 2. The binding affinity of BH3-only peptides to the anti-apoptotic Bcl-2 family members

BH3-only peptides (Top) demonstrate a distinct binding pattern to the anti-apoptotic Bcl-2 family members (Left). Red depicts high affinity binding, orange depicts low- affinity binding and green depicts non-detectable binding. The BH3-only proteins are subdivided into activators and sensitizers. Modified with permission from (Deng et al., 2007).

Fig 3. The apoptotic blocks utilized by cancer cells

In order to evade apoptosis cancer cells select for blocks in apoptotic signaling. These blocks have been categorized based on which group of the BCL-2 family is altered. A class A block is caused by a loss of BH3-only proteins, a Class B block is due to loss or inactivation of BAX and BAK and a class C block is caused by enhanced expression of anti-apoptotic BCL-2 proteins. Following activation and insertion of BAX and BAK into the mitochondrial memberane, the outer mitochondrial membrane is permeabilized (MOMP) enabling release of cytochrome c and activation of apoptosis.

Fig 4. Model of BH3 mimetic- induced apoptosis

Anti-apoptotic Bcl-2 family members buffer the death signals activated by the deregulated growth of cancer cells. BH3 mimetics induce apoptosis by binding to the hydrophobic groove of the anti-apoptotic BCL-2 members displacing bound activator BH3-only proteins, enabling activation of BAX and BAK and the downstream apoptotic events.