title: Enhanced chemopreventive effects of a hydrogen sulfide-releasing anti-inflammatory drug (ATB-346) in experimental colorectal cancer.
abstract: Regular use of nonsteroidal anti-inflammatory drugs is associated with a significantly lower incidence of several types of cancer, particularly those affecting the gastrointestinal tract. However, the propensity of these drugs to cause ulcers and bleeding in the stomach and small intestine limits their utility for chemoprevention of cancer. In the present study, we evaluated the effectiveness of a novel hydrogen sulfide-releasing derivative of naproxen in reducing the incidence of pre-cancerous lesions (aberrant crypt foci) in mice treated with the carcinogen azoxymethane. Weekly administration of azoxymethane over a 4-week period resulted in formation of an average of ∼50 aberrant crypt foci in the colon. Twice-daily treatment with naproxen at high doses significantly reduced the number of aberrant crypt foci. However, a significantly greater effect was observed with ATB-346 (H2S-releasing naproxen) and it was also effective at much lower doses, where naproxen was ineffective. The H2S-releasing moiety of ATB-346 did not significantly affect the number of aberrant crypt foci, suggesting that both the inhibition of cyclooxygenase activity and release of H2S were necessary for the enhanced chemopreventative effect. ATB-346 suppressed colonic prostaglandin synthesis and whole blood thromboxane synthesis as effectively as naproxen, but did not induce any gastrointestinal injury. These results demonstrate that ATB-346 exerts superior chemopreventive effects to those of naproxen, while sparing the gastrointestinal tract of the injury normally associated with use of the parent drug. ATB-346 may therefore be an attractive agent for chemoprevention of colon cancer, and possibly of cancers in other tissues.
authors.affiliation: Farncombe Family Digestive Health Research Institute, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4L8, Canada.
authors.forename: Wagdi
authors.initials: W
authors.lastname: Elsheikh
authors.affiliation: Farncombe Family Digestive Health Research Institute, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4L8, Canada.
authors.forename: Rory W
authors.initials: RW
authors.lastname: Blackler
authors.affiliation: Farncombe Family Digestive Health Research Institute, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4L8, Canada.
authors.forename: Kyle L
authors.initials: KL
authors.lastname: Flannigan
authors.affiliation: Farncombe Family Digestive Health Research Institute, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4L8, Canada; Department of Physiology & Pharmacology, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada. Electronic address: altapharm@hotmail.com.
authors.forename: John L
authors.initials: JL
authors.lastname: Wallace
mesh_terms: D058739:Aberrant Crypt Foci / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D001397:Azoxymethane / Q000633:toxicity; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D015232:Dinoprostone / Q000032:analysis / Q000378:metabolism; D008297:Male; D051379:Mice; D009288:Naproxen / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D020011:Protective Agents / Q000032:analysis / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013929:Thromboxane B2 / Q000097:blood / Q000378:metabolism
chemical_list: C550692:2-(6-methoxy-napthalen-2-yl)-propionic acid 4-thiocarbamoyl-phenyl ester; D000894:Anti-Inflammatory Agents, Non-Steroidal; D020011:Protective Agents; D013929:Thromboxane B2; D009288:Naproxen; D015232:Dinoprostone; D001397:Azoxymethane
keywords: Cancer; Chemoprevention; Colorectal; Cyclooxygenase; Familial adenomatous polypoidosis; Inflammation; Nonsteroidal anti-inflammatory drug; Prostaglandins