Similarly, another major mediator in chronic inflammatory processes is nitric oxide
(NO ), which is produced by liver parenchymal and Selleck SP600125 non-parenchymal cells from l-arginine via nitric oxide synthase (NOS). NO is considered to exert a hepatoprotective action against tissue injury and cytotoxic effects due to invading microorganisms, parasites and tumor cells. However, many situations that cause uncontrolled, prolonged and/or massive production of NO by inducible NOS (iNOS) may result in liver damage, leading to inflammation and even tumor development [26]. iNOS produces much larger amounts of NO and has been detected in many human tumors, such as breast cancer, melanoma, bladder cancer, and colorectal cancer [27], [28], [29] and [30]. A considerable amount of compelling evidence suggests that the inhibition of iNOS and COX-2 expression or activity is important not only for treatment of chronic inflammation, but also for the prevention of cancer [13], [31] and [32]. Therefore, suppression of iNOS and COX-2 induction during cancer progression is recognized as an important and commonly accepted approach to effectively 3-Methyladenine molecular weight inhibit tumor promotion. These biomarkers were highly expressed in liver of DEN/2-AAF-treated animals. Treatment with NX
remarkably suppressed COX-2 and iNOS in DEN/2-AAF-induced animals, suggesting a plausible anti-tumor promotion role of NX in vivo. These results agree with earlier studies that have been shown NX to inhibit prostate, lung and skin cancer cell proliferation by modulation of COX-2 and mafosfamide iNOS inhibition [8], [12] and [13]. PCNA, is a 36 kDa nuclear protein and
its expression in the nucleus is associated with the DNA synthesis phase of cell cycle, and serves as a biomarker of proliferation [20]. Earlier studies have reported that PCNA is highly associated with DEN/2-AAF-induced liver carcinogenesis, which could be detected immunohistochemically [33]. In our study, we found that NX reduced the hepatic PCNA expression in DEN/2-AAF treated rats. Cell cycle regulation is one important mechanism of anti-proliferation in cancers [34]. In the present study, we investigated the cell cycle distribution after treatment with NX and found accumulation of liver cancer cells at G1 phase of cell cycle. Similarly, earlier reports with skin and prostate cancer cells showed NX treatment arrested cell cycle progression at the G0/G1 phase [13]. Studies have also suggested that regulation of cyclin activity plays a key role in cell cycle progression at different phases, in which CDKs are negatively regulated by a group of functionally related proteins known as CDK inhibitors [24]. Cip/p21 binds and inhibits the cyclins E1, D1 and Adependent kinases, regulating the G1 to S phase transition of the cell cycle.
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