A new strategy to block tumor angiogenesis by inhibiting endocannabinoid inactivation

Abstract

Angiogenesis is a key process in the promotion of cancer. Endocannabinoids are endogenous compounds known to mediate psychotropic effects by stimulating the cannabinoid receptor type‐1 (CB1). The present study was carried out to investigate the antiangiogenic effect of the endocannabinoid reuptake inhibitor, OMDM‐2, in comparison with the direct cannabinoid agonist, R‐methanandamide in Ehrlich ascites carcinoma (EAC)‐bearing mice. Solid tumors were induced by intradermal injection of EAC cells that were used for the evaluation of tumor vascular volume using Evan's blue. In addition, tumor weight, serum transforming growth factor‐β1 (TGF‐β1), and its intra‐tumoral receptor (CD‐105) were determined as a time course on days 7, 14, and 21 postinoculation. OMDM‐2 (5 mg/kg, i.p.) significantly reduced the percentage of angiogenesis as efficaciously as R‐Met (0.5 mg/kg, i.p.). On day 7, the treatment with R‐Met or OMDM‐2 significantly down‐regulated CD‐105 expression as evaluated immunohistochemically. Both treatments impeded tumor growth as evident by significant reduction in tumor weight along the study period. The combination with CB‐1 receptor antagonist, NIDA 41020 (0.7 mg/kg, i.p.), counteracted all the previous effects in R‐Met‐treated group but not in OMDM‐2‐treated group. Interestingly, on day 7, the treatment with R‐Met or OMDM‐2 significantly increased serum levels of TGF‐β1, an effect that was not antagonized in both groups by pre‐treatment with NIDA 41020. In conclusion, we have provided for the first time data on the possible in vivo use of OMDM‐2 as an anti‐cancer drug to be an alternative to direct cannabinoid receptor agonists to avoid their CB1‐mediated psychotropic side effects.