Figure 4.

Model of the mechanism of benzodiazepine-mediated cell death. (1) Binding of GABA (agonist) to a Type-A GABA receptor (GABA_AR) “opens” the channel to allow flow of chloride anions out of a cancer cell. This efflux of chloride anions is reflective of the depolarizing nature of the GABA_AR in embryonal cells. (2) Benzodiazepines (positive allosteric modulators of the receptor) enhance the chloride efflux. (3) The significant movement of chloride anions contributes to depolarizing of the mitochondria in the cancer cell and induces mitochondrial fission. This may contribute to mitochondrial dysfunction such as release of reactive oxygen and/or nitrogen, as well as impact ATP production. (4) The p53 signaling pathway is activated in these cancer cells in response to perturbation in ion homeostasis. (5) In addition, the intrinsic (mitochondrial) apoptotic pathway is triggered with an associated role for the pro-apoptotic protein BAD, BCL2 associated agonist of death. (6) In addition to binding to resident GABA_AR on cancer cells, benzodiazepine binds to the GABA_AR on immune cells. This event may contribute to enhanced infiltration of polyfunctional CD8+ T cells and macrophage phagocytosis.