Cell cycle arrest and modulation of HO-1 expression induced by acetyl salicylic acid in hepatocarcinogenesis.
OBJECTIVE
Control of cell proliferation is important for cancer prevention since cell proliferation has an essential role in carcinogenesis. In rodent carcinogenesis models, antioxidant agents suppress carcinogen-induced cellular hyper proliferation in the target organs. Strict control of cell division is an essential process to ensure that DNA synthesis and mitotic division are accurately and coordinately executed. We studied the interplay between cell cycle and heme oxygenase-1 (HO-1) and the effect of the acetylsalicylic acid (ASA) in hepatic carcinogenesis.


METHODS
Male CF1 mice pre-treated with dietary p-dimethylaminoazobenzene (DAB; 0.5%, w/w) were fed with ASA (0.16%, w/w). We investigated the hepatic expression of cyclin D1, cyclin E, Cdk2, Cdk4, p21, p27, p53; the level of bcl-2, an antiapoptotic protein and of heme oxygenase-1 (HO-1), a marker of oxidative stress, by Western blot analysis.


RESULTS
The treatment with ASA produced an important attenuation in the induction of cyclin E and cyclin D1 provoked by DAB. p21 and p27 levels were increased when animals received both drugs. The administration of ASA to DAB treated animals induced Cdk2 (29%). HO-1 induction (65%) provoked by DAB was diminished by ASA administration reaching lower induction levels (23%).


CONCLUSIONS
The deregulation of cyclin/CDK expression and the up-regulation of p21 and p27 with the administration of ASA, post-treatment of the carcinogen administration, would block the pass through out to the G0/G1 check point to permit the cells to repair their DNA and HO-1 protected the liver from reactive oxygen species produced from DAB.
Sacca
P
P
Departamento Química Biológica, Facultad de Ciencias Exactas y Naturales, Centro de Investigaciones sobre Porfirinas y Porfirias (CIPYP), CONICET, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón II, 2do Piso, C1428EHA Buenos Aires, Argentina.
Caballero
F
F
Batlle
A
A
Vazquez
E
E
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D051547:Heme Oxygenase-1; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D020156:Salicylic Acid / Q000494:pharmacology*; D004124:p-Dimethylaminoazobenzene / Q000008:administration & dosage / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D018797:Cell Cycle Proteins; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D004124:p-Dimethylaminoazobenzene; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D020156:Salicylic Acid