Abstract 2142: Plumbagin, a medicinal plant-derived 1,4-napthoquinone, inhibits prostate carcinogenesis in intact and castrated Pten knockout mice by modulation of tumor microenvironment

Abstract

Abstract Prostate specific Pten conditional knockout (PtenLoxP/LoxP:PB-Cre+4) (Pten-KO)) mice are unique preclinical model to evaluate agents for efficacy for both prevention and treatment of PCa. We present here for the first time that dietary plumbagin (PL) inhibits tumor development in intact as well as castrated Pten-KO mice. PL was mixed in an antioxidant free basal powdered diet and was given at two dose levels (200 and 500 ppm). Mice (4 wks old) were divided into three groups (Control (n=40), PL (200 ppm) (n=20), and PL (500 ppm) (n=40). Mice were sacrificed at 15 and 30 wks of age. To determine the prostate tumor volume, we carried out micro-PET/CT analysis of control and PL treated groups mice at 30 wks using a tumor selective radiopharmaceutical agent 124I-NM404. PL treatment (200 and 500 ppm) resulted in a dose-dependent decrease (p<0.01) in prostate tumor volume. PL treatment also resulted in a significant (P<0.001) decrease in weights of prostate tumors and urogenital apparatus at 15 and 30 wks. Histopathological analyses revealed inhibition of prostatic intraepithelial neoplasia (PIN) to invasive adenocarcinoma at 15 and 30 wks. PL treated mice also showed a significant (P<0.01) inhibition of small invasive adenocarcinoma with cystic change at 30 wks. To determine the effects of PL in castrated resistant prostate cancer (CRPC), we castrated 26 Pten-KO mice at 10 wks and divided into 2 groups. PL treatment was started one wk after castration and continued until 50 wks. At 50 wks, castrated control Pten-KO mice illustrated atrophy of prostate tumors. PL treatment (500 ppm) further resulted in a significant decrease of prostate tumors weight of castrated Pten-KO mice. Histopathological analysis of PL treated mice prostate tumors showed significant decrease of both invasive adenocarcinoma and cystic change. Biochemical analyses of Pten-KO mice prostate tumors elicited a constitutive activation of AKT, protein kinase C epsilon (PKCϵ), signal transducer and activators of transcription 3 (Stat3) and increased COX2 expression compared to wild type mice. PL treatment resulted in decreased expression of PKCϵ, Stat3 and COX2 compared to control mice. We also observed that PL targets tumor associated macrophages (TAM) in prostate tumors. Prostate tumors of PL treated mice showed an increased infiltration of M1 macrophages and inhibition of M2 macrophages, as analyzed by immunohistochemical staining of F4/80, iNOS and L-arginase. PL treatment also inhibited the expression of vimentin and slug, the markers of epithelial to mesenchymal transition (EMT) in prostate tumors. In summary, the results indicate that dietary PL inhibits growth of both primary and CRPC, which was accompanied inhibition of EMT and modulation of tumor microenvironment. We conclude that PL may be worthy of evaluation for the prevention and treatment of human PCa (Support: CA138761). Citation Format: Bilal B. Hafeez, Joseph W. Fischer, Ashok Singh, Ala Mustafa, Louise Meske, Ajit K. Verma. Plumbagin, a medicinal plant-derived 1,4-napthoquinone, inhibits prostate carcinogenesis in intact and castrated Pten knockout mice by modulation of tumor microenvironment. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2142. doi:10.1158/1538-7445.AM2014-2142