Organogold Compounds Unleash Cell Death by Opening Mitochondrial Channels

Objectives: We previously screened synthetic organogold compounds for anti-tumor activity and found two that may selectively induce cell death in malignant and premalignant cells compared to normal oral epithelial cells. Here, we aimed to study the mechanism of action of these compounds. We hypothesized that the organogold compounds acted on mitochondria and induced opening of either the mitochondrial apoptosis-induced channel (MAC) or the mitochondrial permeability transition pore (mPTP), which are located in the mitochondrial outer and inner membranes, respectively. Opening of either channel results in release of factors from mitochondria, which causes cell death.
Methods: Bax and/or Bak form MAC during the commitment step of apoptosis. The involvement of MAC in the cytotoxicity of organogold compounds IV and V was assessed in Bak-/-Bax-/- double-knockout (DKO) and parental mouse embryonic fibroblasts (MEF) using alamar blue viability assays. The mechanisms were further investigated by examining several markers for apoptosis and necrosis using fluorescence microscopy, including release of mitochondrial proteins, mitochondrial depolarization and changes in cell shape and nuclear morphology.
Results: Compound IV was more cytotoxic than compound V to both DKO and parental MEFs. However, the effect of compound IV, but not compound V, was substantially attenuated in DKO compared to parental MEFs. These findings suggest that compound IV induces opening of MAC and intrinsic apoptosis. Interestingly, treatment with compound V caused mitochondrial depolarization, which implicated mPTP and necrosis. More experiments are underway to further determine the mechanisms by which MAC and mPTP are induced, especially in cancer cells.
Conclusions: This project is significant because it identifies novel chemotherapy targets, i.e., MAC and mPTP, to increase the efficacy of current cancer treatments. Furthermore, it examines the mechanisms and evaluates the potential of organogold compounds as anti-tumor drugs since at least compound IV selectively kills malignant rather than normal oral epithelial cells.