Anti-cancer mechanisms of COX/LOX inhibitor licofelone on prostate carcinogenesis

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DESCRIPTION (provided by applicant): Licofelone (ML-3000), a new and most interesting compound, is a balanced and competitive inhibitor of both COX and 5-LOX enzymes and has been demonstrated for its potent anti-inflammatory activity. Recent studies have reported on the potential utility of dietary licofelone as an anti-cancer agent for colon and breast cancer chemoprevention. We have demonstrated for the first time that licofelone-mediated COX-2 and 5-LOX inhibition induced apoptosis, and reduced PCa cell proliferation. In addition, we have also observed that licofelone down-regulated several key pro-inflammatory gene targets at the transcription level, such as NF- :Bp65, VEGF and TNF1 in PCa cells. It has also been reported that licofelone induces apoptosis in colon cancer cells through the mitochondrial pathway independent of arachidonic acid. However, to date, the in vivo anti-tumorigenic efficacy or mechanism of licofelone against PCa has not been investigated. Therefore, establishing the efficacy and understanding the underlying mode of action of licofelone in animal models of prostate cancer is very critical for promoting its use as a potential chemopreventive or therapeutic agent. We hypothesize that the dual COX/LOX inhibitor licofelone prevents PCa by acting on a broad- spectrum of anti- cancer mechanisms, including modulation of inflammatory pathway mediators, inhibition of tumor angiogenesis, induction of cell cycle arrest and of caspase-mediated apoptosis, in addition to, or independent of, COX/LOX enzyme inhibition. In view of specific concerns expressed by the reviewers, we have eliminated the cell culture studies and the xenograft model. In this revised application, to test our hypothesis, we now propose to employ a Noble (NBL) rat PCa model in which a combined hormonal regimen treatment that contributes to chronic inflammation leading to initiation, neoplastic conversion and prostate carcinogenesis and is being widely used for intervention studies. We have also proposed novel and innovative technologies, such as use of laser capture microdissection (LCM) for the procurement of cancer cells from specific microscopic regions of malignant lesions for RNA extraction, and pathway-focused microarrays (GEArrays) to determine the expression of altered genes and transcription factors that will provide crucial information to support our hypothesis that licofelone has the potentials to modulate multiple anticancer mechanistic pathways to prevent prostate carcinogenesis. This proposed study is consistent with the scope of the NCI's Program Announcement # PAR-08-055, Cancer Prevention Research Small Grant Program (R03). Considering its excellent safety profile in contrast to the conventional NSAIDs, licofelone offers great potential for preventive interventions in clinical studies for cancer chemoprevention, while minimizing toxicity.