Gold(III) porphyrin 1a induced apoptosis by mitochondrial death pathways related to reactive oxygen species

Apoptosis is a tightly controlled multistep mechanism of cell death, and mitochondria are considered to play a central role in this process. Mitochondria initiate two distinct apoptosis pathways, one caspase-dependent and the other caspase-independent. In addition, mitochondrial production of reactive oxygen species (ROS) seems to play a role in cell death. Most. chemotherapeutic agents induce apoptosis through it least one of these pathways. The post-initiation mechanisms of gold(Ill) porphyrin 1a were investigated in this study. HONE1 cells exposed to gold(l][1) porphyrin lit underwent apoptosis after 24 hours. Functional proteomic studies revealed the alteration of several cytoplasmic protein expressions in HONE1 cells after treatment with the drug. These proteins include enzymes participating in energy production and proteins involved in cellular redox balance. There was a quick attenuation of mitochondrial membrane potential (Delta psi(m)) with the alterations of Bcl-2 family proteins, the release of cytochrome c, and apoptosis-inducing factor (AIF) following gold(III) porphyrin la treatment.. Cytochrome c in turn activated caspase-9 and caspase-3. Cotreatment with caspase inhibitor (zVAD-fmk) showed that the activated caspases worked in conjunction with AIF-initiated apoptosis pathways. Further study showed that ROS played a part in gold(III) porphyrin 1a-induced apoptosis by regulating Delta psi(m). In summary, gold(III) porphyrin la induced apoptosis through both caspase-dependent. and caspase-independent mitochondrial pathways, and intracellular oxidation affected gold(III) porphyrin la-induced apoptosis. These results support it role for gold(Ill) porphyrin la as a promising anticancer drug lead and its a possible novel therapeutic agent directed toward the mitochondria.