Prostaglandin E(2) protects intestinal tumors from nonsteroidal anti-inflammatory drug-induced regression in Apc(Min/+) mice.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are antitumorigenic in humans as well as in animal models of intestinal neoplasia, such as the adenomatous polyposis coli (Min/+) (Apc(Min/+)) mouse. NSAIDs inhibit cyclooxygenase (COX) isozymes, which are responsible for the committed step in prostaglandin biosynthesis, and this has been considered the primary mechanism by which NSAIDs exert their antitumorigenic effects. However, mounting evidence suggests the existence of COX-independent mechanisms. In the present study, we attempted to clarify this issue by treating Apc(Min/+) mice bearing established tumors with NSAIDs (piroxicam and sulindac, 0.5 and 0.6 mg/mouse/day, respectively) for 6 days and concomitantly bypassing COX inhibition by treatment with the E prostaglandin (EP) receptor agonists 16,16-dimethyl-prostaglandin E(2) (PGE(2)) and 17-phenyl-trinor-PGE(2) (10 microg each, three times daily) administered via gavage and/or i.p. routes. Treatment with piroxicam and sulindac resulted in 95% and 52% fewer tumors, respectively, and a higher ratio of apoptosis:mitosis in tumors from sulindac-treated mice as compared with controls. These effects were attenuated by concomitant EP receptor agonist treatment, suggesting PGE(2) is important in the maintenance of tumor integrity. Immunological sequestration of PGE(2) with an anti-PGE(2) monoclonal antibody likewise resulted in 33% fewer tumors in Apc(Min/+) mice relative to untreated controls, additionally substantiating a role for PGE(2) in tumorigenesis. The EP receptor subtype EP1 mediates the effects of PGE(2) by increasing intracellular calcium levels ([Ca(2+)](i)), whereas antagonism of EP1 has been shown to attenuate tumorigenesis in Apc(Min/+) mice. We demonstrate that [Ca(2+)](i) is significantly elevated in tumors of Apc(Min/+) mice relative to the adjacent normal-appearing mucosa. Furthermore, treatment with piroxicam results in significantly lower [Ca(2+)](i) in tumors, and this effect is attenuated by concomitant treatment with the EP1/EP3 receptor agonist 17-phenyl-trinor-PGE(2). Overall, our results suggest that NSAIDs exert their antitumorigenic effects, in part, via interference with PGE(2) biosynthesis, and these effects may be mediated through changes in intracellular calcium levels.
Hansen-Petrik
Melissa B
MB
Department of Nutrition, University of Tennessee, Knoxville, Tennessee 37996, USA.
McEntee
Michael F
MF
Jull
Brian
B
Shi
Hang
H
Zemel
Michael B
MB
Whelan
Jay
J
D015064:16,16-Dimethylprostaglandin E2 / Q000494:pharmacology*; D011125:Adenomatous Polyposis Coli / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000031:analogs & derivatives* / Q000276:immunology / Q000494:pharmacology*; D004195:Disease Models, Animal; D004347:Drug Interactions; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008938:Mitosis / Q000187:drug effects; D010894:Piroxicam / Q000037:antagonists & inhibitors / Q000494:pharmacology; D018078:Receptors, Prostaglandin E / Q000819:agonists; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D013467:Sulindac / Q000037:antagonists & inhibitors / Q000494:pharmacology
C092396:17-phenyltrinorprostaglandin E2; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; D016861:Cyclooxygenase Inhibitors; C545635:PTGER1 protein, human; C545644:PTGER2 protein, human; C545636:Ptger1 protein, mouse; C545645:Ptger2 protein, mouse; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D010894:Piroxicam; D013467:Sulindac; D015232:Dinoprostone; D015064:16,16-Dimethylprostaglandin E2; D002118:Calcium