Novel hexahydrocannabinol analogs as potential anti-cancer agents inhibit cell proliferation and tumor angiogenesis

Abstract

Both natural and synthetic cannabinoids have been shown to suppress the growth of tumor cells in culture and in animal models by affecting key signaling pathways including angiogenesis a pivotal step in tumor growth invasion and metastasis In our search for cannabinoid-like anticancer agents devoid of psychoactive side effects we synthesized and evaluated the anti-angiogenic effects of a novel series of hexahydrocannabinol analogs Among these two analogs LYR-7 [(9S)-3 669 tetramethyl-6a 7 8 9 10 10a-hexahydro-6H-benzo[c]chromen-1-ol] and LYR-8 (1 ((9S)-1-hydroxy 66 9-trimethyl-6a,7 89 10 10a hexahydro-6H benzo[c]chromen-2 yl)ethanone)) were selected based on their anti-angiogenic activity and lack of binding affinity for cannabinoid receptors Both LYR-7 and LYR-8 inhibited VEGF-Induced proliferation migration and capillary-like tube formation of HUVECs in a concentration dependent manner The inhibitory effect of the compounds on cell proliferation was more selective in endothelial cells than in breast cancer cells (MCF 7 and tamoxifen-resistant MCF-7) We also noted effective inhibition of VEGF-induced new blood vessel formation by the compounds in the in vivo chick chorioallantoic membrane (CAM) assay Furthermore both LYR analogs potently inhibited VEGF production and NF-kappa B transcriptional activity in cancer cells Additionally LYR 7 or LYR-8 strongly inhibited breast cancer cell induced angiogenesis and tumor growth Together these results suggest that novel synthetic hexahydrocannabinol analogs LYR-7 and LYR-8 inhibit tumor growth by targeting VEGF-mediated angiogenesis signaling in endothelial cells and suppressing VEGF production and cancer cell growth (C) 2010 Elsevier B V All rights reserved