BCL2 Gene Family and Cancer


The link between apoptosis and cancer emerged when bcl2 was defined as an oncogene that inhibits cell death as opposed to promoting cellular proliferation. This novel discovery for the function of an oncogene gave rise to the concept that impaired apoptosis is a crucial step in tumorigenesis. Dysregulation of apoptosis allows cells to survive in hostile environments (e.g. where cytokines and oxygen are limiting), evolve into more aggressive derivatives that can promote metastasis, and become resistant to chemotherapy.

One of the ultimate goals in cancer research is to learn how to selectively kill cancer cells and spare normal cells. Since cancer cells do not lack the apoptotic machinery but suffer from the loss of regulation of one or more BCL2 family members, the development of pharmacologic compounds to induce apoptosis in cancer cells has therapeutic potential.

 

Early Approaches to Inhibit Anti-Apoptotic Proteins

Early strategies to target anti-apoptotic proteins included antisense oligonucleotides to hybridize and degrade BCL2 mRNA, hence decreasing de novo synthesis of the BCL2 protein. Genasense, an 18-mer phosphorothioate oligonucleotide has been shown to reduce BCL2 protein in xenograft models as well as in clinical trials, though its cytotoxicity may limit its use in combination therapy.

Another strategy to target anti-apoptotic proteins is to activate BAX and BAK by peptides that mimic BH3-only proteins. Using a chemical strategy, termed hydrocarbon stapling, Walensky and colleagues generated BH3 peptides that show selective high-affinity binding to anti-apoptotic proteins. These stabilized α-helix of BCL2 domains (SAHBs) are cell-permeable and protease-resistant and have been shown to activate the apoptotic pathway to kill cancer cells.

 

Therapeutic Potential of BH3 Mimetics

BH3 mimetics are small non-peptide molecules that mimic the binding of BH3- only proteins to anti-apoptotic proteins. The finding that particular BH3 domains preferentially bind particular anti-apoptotic proteins enhances the likelihood to target specific anti-apoptotic proteins most important for maintaining a particular tumor type. That specificity presents the opportunity to efficiently kill tumor cells but limit cytotoxicity to normal cells at the same time. Hence, a drug that could directly interact with specific BCL2 family member(s) to induce cell death would potentially have fewer side effects.

The first BH3 mimetics were discovered as natural compounds that can bind to anti-apoptotic proteins. For example, gossypol is reported to inhibit BCL2 and BCL-XL, though it exhibited high toxicities in phase I clinical trials. The removal of two reactive aldehyde groups results in the less toxic apogossypol. HA14-1 is a chromenederivate that was identified by computer modeling and proposed to inhibit BCL2. 2-methoxy-antimycin A3 was found to antagonize BCL-XL in a similar manner.