J Appl Biomed 14:199-209, 2016 | DOI: 10.1016/j.jab.2016.01.003

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

Valliappan Karuppiaha,b,*, Kumarappan Alagappanc, Kannan Sivakumarb, Lakshmanan Kannanb
a Research Centre for Plant Growth and Development, School of Life Sciences, University of KwaZulu-Natal Pietermaritzburg, Private Bag X 01, Scottsville 3209, South Africa
b CAS in Marine Biology, Faculty of Marine Sciences, Annamalai University, Parangipettai 608502, Tamil Nadu, India
c Accuvis Bio, Abu Dhabi University Campus, Khalifa City B, Abu Dhabi, United Arab Emirates

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.

Keywords: Phenazine-1-carboxylic acid; Streptomyces; Prostate cancer; Programmed cell death; Reactive oxygen species; Mitochondria

Received: October 10, 2015; Revised: January 11, 2016; Accepted: January 11, 2016; Published: August 1, 2016  Show citation

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Karuppiah V, Alagappan K, Sivakumar K, Kannan L. 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. J Appl Biomed. 2016;14(3):199-209. doi: 10.1016/j.jab.2016.01.003.
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