A study presented at the AACR 101st Annual Meeting 2010 by researchers from the Fox Chase Cancer Center, Philadelphia, Pennsylvania, provides further evidence that non-steroidal anti-inflammatory drugs (NSAIDs) are promising chemopreventive agents with activity against colorectal cancer. The study, which was presented by Margie Clapper, PhD, found that nitric oxide-donating naproxen (NO-naproxen), an investigational form of naproxen, can block one of the earliest molecular changes that leads to colorectal cancer. In addition, unlike many NSAIDs, this formulation has demonstrated reduced gastrointestinal toxicity.
Earlier studies had shown that dysregulation of the Wnt/β-catenin pathway is one of the earliest events during tumorigenesis in the colon. To test whether NO-naproxen could reduce activation of the pathway, the team treated human SW480 colon carcinoma cells expressing mutant APC to become bioluminescent when the Wnt/β-catenin pathway is active. Thereafter, the cells were treated with 0.01 to 0.4 mM naproxen or NO-naproxen or vehicle (water or dimethylsulpheroxide). Once the cells were harvested 48 hours later, testing revealed that NO-naproxen reduced β-catenin-mediated TCF4 transcriptional activity in the SW480 cells in a dose-dependent manner, with cells treated with NO-naproxen having about 50% less bioluminescence than cells treated with naproxen. “The major and novel finding from the study is that the NO-naproxen can alter a particular signaling pathway that is one of the earliest events in colon cancer formation,” said Clapper in a press statement. “Based on the in vitro data, we think that NO-naproxen is much better than naproxen in nipping this whole process in the bud,” she added.
Based on the promising in vitro findings, Clapper and her team have treated mice that are genetically predisposed to developing colorectal adenomas with NO-naproxen and naproxen, and are awaiting the results of this study. Clapper noted that this mouse model provides a unique opportunity to compare the efficacy of these agents against colorectal tumor growth in vivo.
AACR ABSTRACT 5695 (http://bit.ly/bDN4kg