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Antiangiogenic activity of the endocannabinoid anandamide: correlation to its tumor-suppressor efficacy.
J Cell Physiol. 2007 May; 211(2):495-503.JC

Abstract

Endocannabinoids are now emerging as suppressors of key cell-signaling pathways involved in cancer cell growth, invasion, and metastasis. We have previously observed that the metabolically stable anandamide analog, 2-methyl-2'-F-anandamide (Met-F-AEA) can inhibit the growth of thyroid cancer in vivo. Our hypothesis was that the anti-tumor effect observed could be at least in part ascribed to inhibition of neo-angiogenesis. Therefore, the aim of this study was to assess the anti-angiogenic activity of Met-F-AEA, to investigate the molecular mechanisms underlying this effect and whether Met-F-AEA could antagonize tumor-induced endothelial cell sprouting. We show that Met-F-AEA inhibited bFGF-stimulated endothelial cell proliferation, in a dose-dependent manner, and also induced apoptosis, both effects reliant on cannabinoid CB1 receptor stimulation. Analyzing the signaling pathways implicated in angiogenesis, we observed that the bFGF-induced ERK phosphorylation was antagonized by Met-F-AEA, and we found that p38 MAPK was involved in Met-F-AEA-induced apoptosis. Moreover, Met-F-AEA was able to inhibit bi-dimensional capillary-like tube formation and activity of matrix metalloprotease MMP-2, a major matrix degrading enzyme. Importantly, we demonstrated that Met-F-AEA is also functional in vivo since it inhibited angiogenesis in the chick chorioallantoic neovascularization model. Finally, Met-F-AEA inhibited tumor-induced angiogenesis in a three-dimensional model of endothelial and thyroid tumor cell (KiMol) spheroids co-cultures in different 3-D polymeric matrices that resemble tumor microenvironment and architecture. Thus, our results suggest that anandamide could be involved in the control of cancer growth targeting both tumor cell proliferation and the angiogenic stimulation of the vasculature.

Authors+Show Affiliations

Department of Pharmaceutical Sciences, University of Salerno, Fisciano, Salerno, Italy.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17192847

Citation

Pisanti, Simona, et al. "Antiangiogenic Activity of the Endocannabinoid Anandamide: Correlation to Its Tumor-suppressor Efficacy." Journal of Cellular Physiology, vol. 211, no. 2, 2007, pp. 495-503.
Pisanti S, Borselli C, Oliviero O, et al. Antiangiogenic activity of the endocannabinoid anandamide: correlation to its tumor-suppressor efficacy. J Cell Physiol. 2007;211(2):495-503.
Pisanti, S., Borselli, C., Oliviero, O., Laezza, C., Gazzerro, P., & Bifulco, M. (2007). Antiangiogenic activity of the endocannabinoid anandamide: correlation to its tumor-suppressor efficacy. Journal of Cellular Physiology, 211(2), 495-503.
Pisanti S, et al. Antiangiogenic Activity of the Endocannabinoid Anandamide: Correlation to Its Tumor-suppressor Efficacy. J Cell Physiol. 2007;211(2):495-503. PubMed PMID: 17192847.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Antiangiogenic activity of the endocannabinoid anandamide: correlation to its tumor-suppressor efficacy. AU - Pisanti,Simona, AU - Borselli,Cristina, AU - Oliviero,Olimpia, AU - Laezza,Chiara, AU - Gazzerro,Patrizia, AU - Bifulco,Maurizio, PY - 2006/12/29/pubmed PY - 2007/5/16/medline PY - 2006/12/29/entrez SP - 495 EP - 503 JF - Journal of cellular physiology JO - J Cell Physiol VL - 211 IS - 2 N2 - Endocannabinoids are now emerging as suppressors of key cell-signaling pathways involved in cancer cell growth, invasion, and metastasis. We have previously observed that the metabolically stable anandamide analog, 2-methyl-2'-F-anandamide (Met-F-AEA) can inhibit the growth of thyroid cancer in vivo. Our hypothesis was that the anti-tumor effect observed could be at least in part ascribed to inhibition of neo-angiogenesis. Therefore, the aim of this study was to assess the anti-angiogenic activity of Met-F-AEA, to investigate the molecular mechanisms underlying this effect and whether Met-F-AEA could antagonize tumor-induced endothelial cell sprouting. We show that Met-F-AEA inhibited bFGF-stimulated endothelial cell proliferation, in a dose-dependent manner, and also induced apoptosis, both effects reliant on cannabinoid CB1 receptor stimulation. Analyzing the signaling pathways implicated in angiogenesis, we observed that the bFGF-induced ERK phosphorylation was antagonized by Met-F-AEA, and we found that p38 MAPK was involved in Met-F-AEA-induced apoptosis. Moreover, Met-F-AEA was able to inhibit bi-dimensional capillary-like tube formation and activity of matrix metalloprotease MMP-2, a major matrix degrading enzyme. Importantly, we demonstrated that Met-F-AEA is also functional in vivo since it inhibited angiogenesis in the chick chorioallantoic neovascularization model. Finally, Met-F-AEA inhibited tumor-induced angiogenesis in a three-dimensional model of endothelial and thyroid tumor cell (KiMol) spheroids co-cultures in different 3-D polymeric matrices that resemble tumor microenvironment and architecture. Thus, our results suggest that anandamide could be involved in the control of cancer growth targeting both tumor cell proliferation and the angiogenic stimulation of the vasculature. SN - 0021-9541 UR - https://www.unboundmedicine.com/medline/citation/17192847/Antiangiogenic_activity_of_the_endocannabinoid_anandamide:_correlation_to_its_tumor_suppressor_efficacy_ L2 - https://doi.org/10.1002/jcp.20954 DB - PRIME DP - Unbound Medicine ER -