title: Graviola inhibits hypoxia-induced NADPH oxidase activity in prostate cancer cells reducing their proliferation and clonogenicity.
abstract: Prostate cancer (PCa) is the leading malignancy among men. Importantly, this disease is mostly diagnosed at early stages offering a unique chemoprevention opportunity. Therefore, there is an urgent need to identify and target signaling molecules with higher expression/activity in prostate tumors and play critical role in PCa growth and progression. Here we report that NADPH oxidase (NOX) expression is directly associated with PCa progression in TRAMP mice, suggesting NOX as a potential chemoprevention target in controlling PCa. Accordingly, we assessed whether NOX activity in PCa cells could be inhibited by Graviola pulp extract (GPE) that contains unique acetogenins with strong anti-cancer effects. GPE (1-5 μg/ml) treatment strongly inhibited the hypoxia-induced NOX activity in PCa cells (LNCaP, 22Rv1 and PC3) associated with a decrease in the expression of NOX catalytic and regulatory sub-units (NOX1, NOX2 and p47(phox)). Furthermore, GPE-mediated NOX inhibition was associated with a strong decrease in nuclear HIF-1α levels as well as reduction in the proliferative and clonogenic potential of PCa cells. More importantly, GPE treatment neither inhibited NOX activity nor showed any cytotoxicity against non-neoplastic prostate epithelial PWR-1E cells. Overall, these results suggest that GPE could be useful in the prevention of PCa progression via inhibiting NOX activity.
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, 12850 E. Montview Blvd, C238, Aurora, CO 80045, USA.|University of Colorado Cancer Center, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Gagan
authors.initials: G
authors.lastname: Deep
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, 12850 E. Montview Blvd, C238, Aurora, CO 80045, USA.
authors.forename: Rahul
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, 12850 E. Montview Blvd, C238, Aurora, CO 80045, USA.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Jain
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, 12850 E. Montview Blvd, C238, Aurora, CO 80045, USA.
authors.forename: Deepanshi
authors.initials: D
authors.lastname: Dhar
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, 12850 E. Montview Blvd, C238, Aurora, CO 80045, USA.
authors.forename: Gati K
authors.initials: GK
authors.lastname: Panigrahi
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, 12850 E. Montview Blvd, C238, Aurora, CO 80045, USA.|Department of Molecular Biology and Biotechnology, Tezpur University, Tezpur, Assam, India.
authors.forename: Anowar
authors.initials: A
authors.lastname: Hussain
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, 12850 E. Montview Blvd, C238, Aurora, CO 80045, USA.|University of Colorado Cancer Center, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Chapla
authors.initials: C
authors.lastname: Agarwal
authors.affiliation: Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina, USA.
authors.forename: Tamam
authors.initials: T
authors.lastname: El-Elimat
authors.affiliation: Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina, USA.
authors.forename: Vincent P
authors.initials: VP
authors.lastname: Sica
authors.affiliation: Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina, USA.
authors.forename: Nicholas H
authors.initials: NH
authors.lastname: Oberlies
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, 12850 E. Montview Blvd, C238, Aurora, CO 80045, USA.|University of Colorado Cancer Center, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Agarwal
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology; D000818:Animals; D029061:Annonaceae / Q000737:chemistry; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008822:Mice, Transgenic; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism*; D000074624:NADPH Oxidase 1; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D010936:Plant Extracts / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D008562:Membrane Glycoproteins; D010936:Plant Extracts; D009247:NADH, NADPH Oxidoreductases; C488842:Cybb protein, mouse; D000074624:NADPH Oxidase 1; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C000614711:NOX1 protein, mouse