Methanandamide increases COX-2 expression and tumor growth in murine lung cancer.
Increased COX-2 expression and elevated PGE2 have been associated with a poor prognosis in lung cancer. Cannabinoids have been known to exert some of their biological effects via modulation of prostaglandin production. We evaluated the impact of methanandamide on COX-2 expression, PGE2 production, and tumor growth in murine lung cancer. Methanandamide administration (5 mg/kg, four times/wk i.p.) resulted in an increased rate of tumor growth (P<0.01 compared with diluent treated controls). The CB1 and CB2 receptor antagonists, SR141716 and SR144528, did not block the methanandamide-mediated increase in tumor growth. In vivo, methanandamide treatment increased the production of PGE2 at the tumor site as well as in splenocytes. Consistent with these results, methanandamide increased PGE2 and COX-2 levels in murine lung cancer cells in vitro via a cannabinoid receptor-independent mechanism. The COX-2-specific inhibitor, SC58236, abrogated methanandamide induction of PGE2 production in vitro and blocked methanandamide-enhanced tumor growth in vivo. Furthermore, the p38/MAPK inhibitor, SB203528, and the p42/44 inhibitor, PD98059, blocked methanandamide-mediated induction of PGE2 and COX-2. These results suggest that methanandamide augments tumor growth by a cannabinoid receptor-independent pathway that is associated with the up-regulation of COX-2.
Gardner
Brian
B
UCLA Lung Cancer Research Program, Jonsson Comprehensive Cancer Center, Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at UCLA and VA Greater Los Angeles Healthcare System, Los Angeles, California 90095-1690, USA.
Zhu
Li X
LX
Sharma
Sherven
S
Tashkin
Donald P
DP
Dubinett
Steven M
SM
D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D008175:Lung Neoplasms / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008954:Models, Biological; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D011720:Pyrazoles / Q000494:pharmacology; D043882:Receptors, Cannabinoid / Q000502:physiology; D013154:Spleen / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D000096926:Benzenesulfonamides
D001095:Arachidonic Acids; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D007527:Isoenzymes; D011451:Prostaglandin-Endoperoxide Synthases; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D013449:Sulfonamides; C119130:4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C088155:methanandamide