Phenazine-1-carboxylic acid-induced programmed cell death in human prostate cancer cells is mediated by reactive oxygen species generation and mitochondrial-related apoptotic pathway

• First report on the anticancer activity of phenazine-1-carboxylic acid.
• Phenazine-1-carboxylic acid showed an antitumor activity in prostate cancer cells by reactive oxygen species production and mitochondrial-related apoptotic pathway.
• Phenazine-1-carboxylic activates both the caspase-dependent and caspase-independent programmed cell death pathway.

Phenazine-1-carboxylic acid has extensive pharmacological activity, including antibiotic and immunomodulatory, but the anticancer activity remains unknown. Treatment of prostate cancer cell line (DU145) with phenazine-1-carboxylic acid stimulated inhibition of cell proliferation in concentration- and time-dependent manner. Dual staining confirmed phenazine-1-carboxylic acid stimulated prostate cancer programmed cell death in time-dependent manner. To investigate the exact mechanism, phenazine-1-carboxylic acid-stimulated oxidative stress and mitochondrial-related apoptotic pathway in human prostate cancer cells were examined in this study. Phenazine-1-carboxylic acid increased the generation of reactive oxygen species (ROS) in prostate cancer cell lines, which triggered the pro-apoptotic JNK signaling. Phosphorylated JNK stimulated the depolarization of mitochondrial membrane potential (ΔΨm) and downregulation of anti-apoptotic protein Bcl-2 related with the upregulation of pro-apoptotic protein Bax. Downregulation of anti-apoptotic Bcl-2 family protein in corresponding with loss of ΔΨm, stimulate the increased production of cytochrome c and programmed cell death inducing factor (AIF) from mitochondria, and ultimately induced the caspase-dependent and caspase-independent programmed cell death. Altogether, the present study suggests that phenazine-1-carboxylic acid showed an antitumor activity in prostate cancer cells by reactive oxygen species production and mitochondrial-related apoptotic pathway. The results of the present study offered an insight into the prospective of phenazine-1-carboxylic acid for prostate cancer therapy.

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