Abstract LB-428: Decursin inhibits advanced human prostate tumor xenograft growth involving antiproliferative and antiangiogenic mechanisms

Abstract

Abstract Prostate cancer (PCa) is 2nd leading malignancy in men, and chemopreventive strategies are suggested as a rational approach to control and manage PCa. Recently, we first showed that a coumarin compound, decursin (molecular weight 328), inhibits the growth of different human PCa cells in culture without any considerable effect on normal prostate epithelial cells. Here, we examined its in vivo antitumor efficacy and associated mechanisms in DU145 PCa xenograft in nude mice. When tumor size reached ∼200 mm3 after 30 days of DU145 cells implantation, mice were divided in two groups and given carboxymethyl cellulose (vehicle) or 75 mg decursin/kg body wt in vehicle orally. After 3 days of treatment, three mice from each group were sacrificed to study the short-term effect of decursin on the molecular changes in tumor, while the remaining mice were sacrificed after 4 weeks of decursin treatment. Although, tumor growth inhibition was apparent in 3 days of decursin treatment, it became statistically significant only after one week of the treatment and accounted for 73% (P<0.001) decrease in tumor volume/mouse and 76% (P=0.016) decrease in tumor weight/mouse, without any considerable effect on body weight gain and diet consumption. Immunohistochemical analysis of the tumor showed 41% decrease in cell proliferation, 4-fold increase in apoptosis, 51 and 59% decreases in COX-2 and iNOS levels, and 36 and 43% decreases in VEGFR-1 and VEGF-R2 levels, respectively (all, P<0.05-0.001). Interestingly, even 3 days of decursin treatment showed 18% decrease in cell proliferation, 2-fold increase in apoptosis, 16 and 6% decreases in COX-2 and iNOS levels, and 10 and 18% decreases in VEGFR-1 and VEGFR-2 levels, respectively. In DU145 cell culture, decursin inhibited EGF-induced EGFR-ERK1/2 and Akt signaling and showed decreased levels of CDKs and cyclins, and increased levels of Cip1/p21 and Kip1/p27. For its antiangiogenic mechanisms, decursin (10-40 μM) inhibited HUVEC cell proliferation in regular medium without any considerable effect on cell death, which was accompanied by reduced invasion, migration and tube formation on matrigel, and a decrease in MMP-2 and MMP-9 activities. Overall, these findings show a strong in vivo antitumor efficacy of oral decursin against advanced human prostate tumor growth which could involve inhibition of mitogenic and survival signaling together with antiangiogenic mechanisms. Importantly, decursin did not show any considerable cell death in non-neoplastic prostate epithelial cells, HUVEC cells and normal keratinocytes, but selectively induced apoptosis in PCa cells. Decursin, therefore, could be a novel coumarin antitumor/chemopreventive agent that warrants further investigation for its translational potential in PCa control. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-428.