Gold porphyrin (III) 1a induced apoptosis by caspase dependent and independent mitochondrial death pathways dependent of reactive oxygen species

Abstract

The application of gold (III) complexes as potential antitumor drug lead with higher cytotoxicity and fewer side effects than existing metal antitumor drugs has been actively pursued in recent years. Our previous findings (Che CM et al, Chem. Commun., 14, 1718-1719, and recent data) showed that the gold (III) meso-tetraarylporphyrin 1a induced apoptosis by initiating a series of complex reactions that caused unbalance between pro-apoptotic and anti-apoptotic signals in human carcinoma cell lines. The mechanism of cancer cell apoptosis induced by gold (III) porphyrin 1a was investigated in the current study. Human nasopharyngeal carcinoma cell line (HONE1) exposed to gold (III) porphyrin 1a underwent apoptosis after 24 h, with formation of DNA ladder and cleavage of PARP-1. Proteomic studies revealed the alteration of several cellular protein expressions in cancer cells after treatment with the drug. These proteins include enzymes participated in energy production and proteins involved in cellular redox balance, suggesting that mitochondrion maybe the main target of gold (III) porphyrin 1a. There was a quick attenuation of mitochondrial membrane potential (ΔΨm) with the release of cytochrome c and apoptosis inducing factor (AIF) following gold (III) porphyrin 1a treatment. Cytochrome c in turn activated caspase 9 and caspase 3. Co-treatment with caspase inhibitor (z-VAD.fmk) revealed that the activated caspases acting in conjunction with apoptosis inducing factor initiated the apoptosis pathways. Further study showed that reactive oxygen species was involved in gold (III) porphyrin 1a induced apoptosis. Pretreatment with NAC or BSO altered the process of apoptosis, indicating that oxidative stress was associated with cytotoxicity of gold (III) porphyrin 1a. Taken together of these findings, gold (III) porphyrin 1a induces apoptosis through both caspase-dependent and -independent mitochondrial pathways that initiated by oxidative stress.