title: Plumbagin inhibits prostate cancer development in TRAMP mice via targeting PKCε, Stat3 and neuroendocrine markers.
abstract: Plumbagin (PL), 5-hydroxy-2-methyl-1,4-naphthoquinone, is a quinoid constituent isolated from the roots of the medicinal plant Plumbago zeylanica L. (also known as chitrak). PL has also been found in Juglans regia (English Walnut), Juglans cinerea (whitenut) and Juglans nigra (blacknut). The roots of P. zeylanica have been used in Indian and Chinese systems of medicine for more than 2500 years for the treatment of various types of ailments. We were the first to report that PL inhibits the growth and invasion of hormone refractory prostate cancer (PCa) cells [Aziz,M.H. et al. (2008) Plumbagin, a medicinal plant-derived naphthoquinone, is a novel inhibitor of the growth and invasion of hormone-refractory prostate cancer. Cancer Res., 68, 9024-9032.]. Now, we present that PL inhibits in vivo PCa development in the transgenic adenocarcinoma of mouse prostate (TRAMP). PL treatment (2 mg/kg body weight i.p. in 0.2 ml phosphate-buffered saline, 5 days a week) to FVB-TRAMP resulted in a significant (P < 0.01) decrease in prostate tumor size and urogenital apparatus weights at 13 and 20 weeks. Histopathological analysis revealed that PL treatment inhibited progression of prostatic intraepithelial neoplasia (PIN) to poorly differentiated carcinoma (PDC). No animal exhibited diffuse tumor formation in PL-treated group at 13 weeks, whereas 75% of the vehicle-treated mice elicited diffuse PIN and large PDC at this stage. At 20 weeks, 25% of the PL-treated animals demonstrated diffuse PIN and 75% developed small PDC, whereas 100% of the vehicle-treated mice showed large PDC. PL treatment inhibited expression of protein kinase C epsilon (PKCε), signal transducers and activators of transcription 3 phosphorylation, proliferating cell nuclear antigen and neuroendocrine markers (synaptophysin and chromogranin-A) in excised prostate tumor tissues. Taken together, these results further suggest PL could be a novel chemopreventive agent against PCa.
authors.affiliation: Department of Human Oncology, Wisconsin Institute of Medical Research, Paul Carbone Comprehensive Cancer Center, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53792, USA. hafeez@humonc.wisc.edu
authors.forename: Bilal Bin
authors.initials: BB
authors.lastname: Hafeez
authors.forename: Weixiong
authors.initials: W
authors.lastname: Zhong
authors.forename: Ala
authors.initials: A
authors.lastname: Mustafa
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Fischer
authors.forename: Olya
authors.initials: O
authors.lastname: Witkowsky
authors.forename: Ajit K
authors.initials: AK
authors.lastname: Verma
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D000952:Antigens, Polyomavirus Transforming / Q000032:analysis; D053379:Chromogranin A / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009285:Naphthoquinones / Q000627:therapeutic use*; D010766:Phosphorylation; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D011471:Prostatic Neoplasms / Q000473:pathology / Q000517:prevention & control*; D051744:Protein Kinase C-epsilon / Q000037:antagonists & inhibitors*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*; D016708:Synaptophysin / Q000037:antagonists & inhibitors*
chemical_list: D016588:Anticarcinogenic Agents; D000952:Antigens, Polyomavirus Transforming; D053379:Chromogranin A; D009285:Naphthoquinones; D018809:Proliferating Cell Nuclear Antigen; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D016708:Synaptophysin; C569015:Syp protein, mouse; C497256:Prkce protein, mouse; D051744:Protein Kinase C-epsilon; C014758:plumbagin