Inhibition of chronic ulcerative colitis-associated colorectal adenocarcinoma development in a murine model by N-acetylcysteine.
Long-term ulcerative colitis (UC) patients are at increased risk for developing colorectal cancer. In order to develop strategies for preventing UC-associated carcinogenesis, we studied the effect of the antioxidant N-acetylcysteine (NAC) on UC-associated cancer development in a mouse model. Female C57BL/6J mice were subjected to long-term administration of dextran sulfate sodium (DSS) in the drinking fluid and 2-fold iron-enriched AIN76A diet, with or without NAC. In the DSS-plus-2-fold iron positive control group, gross tumor incidence was 88.5% (23/26 mice) after 12 DSS cycles (1 DSS cycle = 7 day DSS treatment period followed by 10 day recovery period). The tumor multiplicity was 2.1 +/- 0.2 tumors/tumor-bearing mouse, and the tumor volume was 0.054 +/- 0.019 cm3. With 0.2% NAC administration, tumor incidence was significantly reduced (68%, 17/25 mice; P < 0.05), as was the tumor multiplicity (1.5 +/- 0.1 tumors/tumor-bearing mouse; P < 0.05). The tumor volume was lower (0.014 +/- 0.004 cm3), but not significantly decreased. The proliferation index was significantly decreased in non-cancerous epithelia (48.5 +/- 6.0% vs 32.0 +/- 3.7%; P < 0.05), but not in tumor cells. NAC significantly induced apoptosis in both non-cancerous epithelia and colorectal adenocarcinoma. The number of cells immunostained-positive for nitrotyrosine was markedly decreased in the non-cancerous mucosa of NAC-treated mice (102.4 +/-16.6 positive cells/mm2 mucosa vs 53.6 +/- 14.9 cells/mm2; P < 0.05). In addition, the number of inducible nitric oxide synthase (iNOS)-positive inflammatory cells in the non-cancerous mucosa of the distal colon was markedly decreased by NAC. This study indicates that the antioxidant NAC has the potential to serve as a preventive agent for UC-associated colorectal cancer, possibly via inhibition of cellular proliferation and nitrosative stress-caused cellular damage.
Seril
Darren N
DN
Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, College of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854-8020, USA.
Liao
Jie
J
Ho
Kwok-Lam K
KL
Yang
Chung S
CS
Yang
Guang-Yu
GY
D000111:Acetylcysteine / Q000494:pharmacology*; D000230:Adenocarcinoma / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D003093:Colitis, Ulcerative / Q000150:complications / Q000517:prevention & control*; D015179:Colorectal Neoplasms / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL
D016588:Anticarcinogenic Agents; D000975:Antioxidants; D000111:Acetylcysteine