Cannabinoids and their receptors agonists are drawing renewed attention as potential anti-tumor agents. Recently, we have shown that expression levels of both cannabinoid receptors CB1 and CB2 are higher in human prostate cancer cells than in normal prostate epithelial cells (Cancer Res. 65:1635-41, 2005) and observed that sustained activation of ERK1/2 by cannabinoid receptors agonist WIN-55,212-2 (WIN) leads to G1 cell cycle arrest and apoptosis in LNCaP cells (J. Biol. Chem.,PMID: 17068343). To establish in vivo relevance of these in vitro findings, we implanted athymic nude mice with androgen-responsive CWR22Rν1 cells which form rapid tumors and secrete PSA in the blood stream of the host. As compared to untreated animals, WIN treated mice (0.5 mg/kg b.wt, i.p, alternate day) exhibited significant inhibition in the tumor growth with significant reduction in PSA secretion in the serum. In animals without WIN treatment, targeted tumor volume of 1200 mm3 was reached at 35 days post-tumor inoculation; whereas this tumor volume was attained in 51 days in WIN treated mice. Since angiogenesis is an essential component to primary tumor growth and metastasis, we next assessed the effect of WIN treatment on the markers of cell proliferation, angiogenesis and metastasis. Protein expression of PCNA, a marker of cell proliferation was considerably lower (45%) in tumors of WIN treated mice as compared to untreated animals. Protein expression of angiopoetins and VEGF, members of the vascular endothelial growth factor family that participate in the formation of blood vessels were also evaluated. Tumor tissues from WIN treated mice had notably lower expression of both angiopoetin-1 (41%) and angiopoetin-2 (38%) and showed marked decrease (47%) in the expression of VEGF positive cells. Loss of function of E-cadherin is associated with progression of cancer by increasing proliferation, invasion, and/or metastasis. We observed that in WIN treated mice E-cadherin expression was 2.5 fold higher as compared to untreated animals. We also found a decrease in the protein expression of cadherin associated proteins β-catenin and α-catenin in tumors of mice treated with WIN. In the next series of experiments we determined the effect of WIN on the expression of proteins involved in metastasis. The balancebetween matrix metalloproteinases (MMP) and their tissue inhibitors (TIMP) is an essential factor in the aggressiveness of severalcancers. We observed that MMP to TIMP ratioin WIN treated mice was tilted towards TIMP expression suggesting inhibition of MMP expression. Here, we provide in vivo evidence for potential use of cannabinoid receptors agonist for slowing tumor growth of androgen sensitive cells in a xenograft model.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA