title: FAAH inhibition enhances anandamide mediated anti-tumorigenic effects in non-small cell lung cancer by downregulating the EGF/EGFR pathway.
abstract: The endocannabinoid anandamide (AEA), a neurotransmitter was shown to have anti-cancer effects. Fatty acid amide hydrolase (FAAH) metabolizes AEA and decreases its anti-tumorigenic activity. In this study, we have analyzed the role of FAAH inhibition in non-small cell lung cancer (NSCLC). We have shown that FAAH and CB1 receptor which is activated by AEA are expressed in lung adenocarcinoma patient samples and NSCLC cell lines A549 and H460. Since the synthetic analogue of anandamide (Met-F-AEA) did not possess significant anti-tumorigenic effects, we used Met-F-AEA in combination with FAAH inhibitor URB597 which significantly reduced EGF (epidermal growth factor)-induced proliferative and chemotactic activities in vitro when compared to anti-tumorigenic activity of Met-F-AEA alone. Further analysis of signaling mechanisms revealed that Met-F-AEA in combination with URB597 inhibits activation of EGFR and its downstream signaling ERK, AKT and NF-kB. In addition, it inhibited MMP2 secretion and stress fiber formation. We have also shown that the Met-F-AEA in combination with URB597 induces G0/G1 cell cycle arrest by downregulating cyclin D1 and CDK4 expressions, ultimately leading to apoptosis via activation of caspase-9 and PARP. Furthermore, the combination treatment inhibited tumor growth in a xenograft nude mouse model system. Tumors derived from Met-F-AEA and URB597 combination treated mice showed reduced EGFR, AKT and ERK activation and MMP2/MMP9 expressions when compared to Met-F-AEA or URB597 alone. Taken together, these data suggest in EGFR overexpressing NSCLC that the combination of Met-F-AEA with FAAH inhibitor resulted in superior therapeutic response compared to individual compound activity alone.
authors.affiliation: Department of Pathology, The Ohio State University, Ohio, USA.
authors.forename: Janani
authors.initials: J
authors.lastname: Ravi
authors.forename: Amita
authors.initials: A
authors.lastname: Sneh
authors.forename: Konstantin
authors.initials: K
authors.lastname: Shilo
authors.forename: Mohd W
authors.initials: MW
authors.lastname: Nasser
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Ganju
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001095:Arachidonic Acids / Q000494:pharmacology*; D015153:Blotting, Western; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002633:Chemotaxis; D019008:Drug Resistance, Neoplasm; D063388:Endocannabinoids / Q000494:pharmacology*; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D053284:Polyunsaturated Alkamides / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D046888:Tissue Array Analysis; D014407:Tumor Cells, Cultured; D014945:Wound Healing / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001095:Arachidonic Acids; D002121:Calcium Channel Blockers; D063388:Endocannabinoids; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D016328:NF-kappa B; D053284:Polyunsaturated Alkamides; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D043884:Receptor, Cannabinoid, CB1; D000099252:Fatty Acid Amide Hydrolases; C512478:EGFR protein, human; C078814:anandamide