Narayanan, Bhagavathi A. published the artcileRegression of mouse prostatic intraepithelial neoplasia by nonsteroidal anti-inflammatory drugs in the transgenic adenocarcinoma mouse prostate model, Name: Sulindac sulfone, the publication is Clinical Cancer Research (2004), 10(22), 7727-7737, database is CAplus and MEDLINE.
Epidemiol. studies have revealed a decreased risk of colon cancer among people who have regularly taken cyclooxygenase (COX)-2 inhibitors such as aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs). Whereas the selective COX-2 inhibitor celecoxib and exisulind, a metabolic product of sulindac, have gained increasing attention as efficacious chemopreventive agents against colon and prostate cancer, not much is known about the underlying mol. targets and mechanisms. Moreover, the side effects of NSAIDs are a major obstacle for large-scale application to the prevention of cancer in humans; for example, in the United States in 1998, there were 16,550 deaths from NSAID-induced gastrointestinal complications. The toxicity associated with these compounds is raising concerns, and more needs to be known about their mode of action and mol. targets. We used the transgenic mouse prostate (TRAMP) model, which exhibits similarities with human prostate cancer, including epithelial origin, progression from the PIN stage to adenocarcinoma, and metastasis by a transgene that is hormonally regulated by androgens. In addition to histol. analyzing the PIN lesions of the dorsolateral prostate from TRAMP mice, we delineated the mol. targets and mechanisms of celecoxib and exisulind against mouse PIN lesions. We performed Western blot anal. of the total protein lysate from the tissues of mouse PIN lesions to measure the level of expression of androgen receptor, vascular endothelial growth factor, nuclear factor-κB p65, BclII, AKT (total and phosphorylated Ser473), p53, cyclin-dependent kinase inhibitor p21WAF1/CIP1, p27, BAX, and caspase-3 to demonstrate the COX-2-independent mechanism involved in the inhibition of PIN lesions of the dorsolateral prostate by both celecoxib and exisulind. We found for the first time that (a) both celecoxib and exisulind as dietary supplements induce strong inhibitory effects against prostate cancer at doses of 800 and 500 ppm, resp., after 16 wk; (b) the histol. anal. of the dorsolateral prostate after 2 wk of treatment indicated a reduction of PIN lesions from 75% to 19% with celecoxib and to 16% with exisulind; (c) more importantly, those few PINs and adenocarcinomas in the groups treated with celecoxib or exisulind showed more apoptotic cells, lower levels of proliferating cell nuclear antigen, and a lower number of mitotic cells. To understand the mol. mechanisms involved in the inhibition of PIN lesions, first, we examined the expression of mol. targets involved in angiogenesis and inflammatory processes. It was clearly evident from Western blot anal. of the total protein lysate derived from the dorsolateral prostate tissues with PIN lesions that expression of androgen receptor, vascular endothelial growth factor, nuclear factor-κB p65, and BclII is down-regulated more effectively by celecoxib. Down-regulation of AKT protein (total and phosphorylated at Ser473) signaling by celecoxib clearly indicates an inhibition of the survival gene and the pathol. process that could otherwise lead to adenocarcinoma. Overall, the findings from this study clearly show the effectiveness of celecoxib and exisulind in reducing the PIN lesions by modulating a cascade of mol. targets involved in COX-2-dependent and -independent mechanisms. Whereas these agents are already in clin. trial or in use as chemopreventive agents, findings from this study demonstrate the difference in their mode of action, thus helping us to understand the side effects.
Clinical Cancer Research published new progress about 59973-80-7. 59973-80-7 belongs to naphthyridine, auxiliary class Immunology/Inflammation,COX, name is Sulindac sulfone, and the molecular formula is C20H17FO4S, Name: Sulindac sulfone.
Referemce:
https://en.wikipedia.org/wiki/1,8-Naphthyridine,
1,8-Naphthyridine | C8H6N2 – PubChem