Control of apoptic pathway by the Bcl-2 protein family. The diverse subclasses of the Bcl-2 protein family serve to manage the homeostasis of mitochondrial-mediated cell death through cooperation with each other (Figure 1.A) (1,5). Moreover, the lack of Bcl-2 regulation is involved in many disorders such as autoimmune disorders and many cancers (2).
Understanding the biology of Bcl-2 protein family is important in cancer therapy (3, 4). The anti-apoptic Bcl-2 inhibits apoptosis by two main mechanisms. The first is a mitochondrial pathway where Bcl-2 inhibits the movement of pro-apoptic proteins BAK and BAX, which undergo oligomerization that lead to outer mitochondrial membrane (OMM) permeabilization and cytochrome c release. This, in…show more content… PKA activates IP3R1 activity, while PP1 inhibits it. Bcl-2 competes with IP3R1 for the binding of PP1 and thus reduces the IP3-mediated calcium signal and protects cells from its death (12).
Design of anticancer drugs that block the anti-apoptic activity of Bcl-2 protein.
By understanding the mechanism of how anti-apoptic Bcl-2 regulates apoptosis, the development of small molecule antagonists have been extensively explored (13). As we mentioned above, Bcl-2 inhibits apoptosis by two different mechanisms, but only the mitochondrial pathway has been successfully targeted by distinct therapeutic agents (8).
Many BH3- mimetic drugs (or competitive inhibitors) have been developed to target the hydrophobic pocket of Bcl-2, liberating BH3- only protein Bim, thereby activating pro-apoptic proteins BAK and BAX (14, 15, 16). These include:
Abt-737 is a BH3- mimetic drug, which has been used in clinical trials to treat both hematological malignancies and solid tumor (10). Abt-263 (navitoclax) is the oral form of Abt-737 that has been shown to have an impact on platelet survival (15, 16). Moreover, ABT-263 has been used in clinical trials in some Bcl-2 dependent hematological cancers, chronic lymphocytic leukemia, lymphoma, and solid tumor (8,10,13), but it showed limited activity in small cell lung cancer (SCLC) (8)
Abt-199 (Venetoclax), another BH3- mimetic drug, which reengineered from Abt-263 (navitoclax) has