Synthetic cannabinoid receptor agonists inhibit tumor growth and metastasis of breast cancer.
Cannabinoids have been reported to possess antitumorogenic activity. Not much is known, however, about the effects and mechanism of action of synthetic nonpsychotic cannabinoids on breast cancer growth and metastasis. We have shown that the cannabinoid receptors CB1 and CB2 are overexpressed in primary human breast tumors compared with normal breast tissue. We have also observed that the breast cancer cell lines MDA-MB231, MDA-MB231-luc, and MDA-MB468 express CB1 and CB2 receptors. Furthermore, we have shown that the CB2 synthetic agonist JWH-133 and the CB1 and CB2 agonist WIN-55,212-2 inhibit cell proliferation and migration under in vitro conditions. These results were confirmed in vivo in various mouse model systems. Mice treated with JWH-133 or WIN-55,212-2 showed a 40% to 50% reduction in tumor growth and a 65% to 80% reduction in lung metastasis. These effects were reversed by CB1 and CB2 antagonists AM 251 and SR144528, respectively, suggesting involvement of CB1 and CB2 receptors. In addition, the CB2 agonist JWH-133 was shown to delay and reduce mammary gland tumors in the polyoma middle T oncoprotein (PyMT) transgenic mouse model system. Upon further elucidation, we observed that JWH-133 and WIN-55,212-2 mediate the breast tumor-suppressive effects via a coordinated regulation of cyclooxygenase-2/prostaglandin E2 signaling pathways and induction of apoptosis. These results indicate that CB1 and CB2 receptors could be used to develop novel therapeutic strategies against breast cancer growth and metastasis.
Qamri
Zahida
Z
Department of Pathology, Ohio State University Medical Center, Columbus, OH 43210, USA.
Preet
Anju
A
Nasser
Mohd W
MW
Bass
Caroline E
CE
Leone
Gustavo
G
Barsky
Sanford H
SH
Ganju
Ramesh K
RK
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D048588:Benzoxazines / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002186:Cannabinoids / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D016513:Mice, SCID; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009025:Morpholines / Q000494:pharmacology*; D009281:Naphthalenes / Q000494:pharmacology*; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000096:biosynthesis / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
D048588:Benzoxazines; D002186:Cannabinoids; D009025:Morpholines; D009281:Naphthalenes; D034741:RNA, Small Interfering; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D051546:Cyclooxygenase 2; D015232:Dinoprostone; C432747:1,1-dimethylbutyl-1-deoxy-Delta(9)-THC