Alpha-fetoprotein promoter-driven Bcl-2-interacting killer double mutant (AFP-BikDD)

The Alpha-fetoprotein (AFP) promoter-driven BikDD system is a targeted gene therapy approach designed for the treatment of hepatocellular carcinoma (HCC). This strategy utilizes the AFP promoter to drive the expression of BikDD, a constitutively active, double-mutant form (T33D/S35D) of the pro-apoptotic BH3-only protein BIK (Zou et al., 2002, Cancer Research). The AFP promoter ensures that the therapeutic protein is expressed selectively in AFP-positive cancer cells, minimizing damage to healthy adult liver tissue where the promoter is inactive (Xie et al., 2007, Gene Therapy). Once produced, the BikDD protein binds with high affinity to anti-apoptotic Bcl-2 family members, such as Bcl-xL, Bcl-2, and Mcl-1, neutralizing their survival-promoting functions (Li et al., 2011, Molecular Cancer Therapeutics). This inhibition leads to the release of pro-apoptotic factors from the mitochondria, activating the caspase cascade and inducing programmed cell death in the tumor cells. This approach is particularly relevant for HCC, which often overexpresses anti-apoptotic proteins to evade cell death and resist conventional therapies. Preclinical studies have demonstrated that this strategy can effectively inhibit tumor growth and sensitize cancer cells to other treatments like sorafenib.

Other names

AFP-BikDDVISA-BikDDBik-T33D/S35DBcl-2-interacting killer double mutantAFP-BIK(T33D/S35D)

Selective transcriptional activation of the pro-apoptotic BikDD protein in AFP-positive cells, which then antagonizes anti-apoptotic Bcl-2 family proteins (Bcl-xL, Bcl-2, Mcl-1) to induce the intrinsic apoptotic pathway.