Research Projects

Numerous experimental, epidemiologic, and clinical studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) have promise as anticancer agents. Combination of anti-inflammatory agents with chemotherapeutic drugs showed cancer prevention, additive or synergistic effects by chemosensitization, and reduced toxicities of chemotherapeutics. These effects are primarily mediated by interfering tumor microenvironment through COX-independent mechanisms, however prolonged use of these agents leads to kidney failure, increased risk of cardio-toxicity due to COX-inhibition. These side effects drive further research on reducing the COX inhibition effects while retaining or potentiating the antitumor efficacy. Preclinical studies show that novel celecoxib based analogues which are not specific to COX-2 also endowed a significant efficacy and reduced toxicity in cancer cells in vitro, in vivo. Selenium and organoselenium molecules acts as both anti-oxidants and pro-oxidants depending upon cellular redox environment. This peculiar nature enables potentiating of the biological effects when it is included in bioactive molecules. As the cancer cells have less efficient anti-oxidant machinery, organoseleniums scavenge Elevated Reactive Oxygen Species (ROS) thereby exerting antitumor activity, concurrently pro-oxidant property promotes ROS to kill cancer cells. The sensitivity of tumor cells to Se-compounds has been observed in many studies, for instance, Se-incorporated combrestatin-A4 analogs have potent anti- proliferative activity over combrestatin-A4. Similarly, Inclusion of selenocyanate pharmacophore into aspirin and celecoxib resulted in the hybrid Se-aspirin and Selenocoxib analogues respectively. These compounds reduced COX-2, TNF-α at the transcription level, and reduced the levels of anti-apoptotic proteins Bcl-2, p-AKT in colorectal, prostate cancer cell lines. Therefore, we envisage that synthesis of Selenated derivatives of anti-inflammatory scaffolds yields chemo-protective and chemo-sensitizing agents. The chemical properties of Se (i.e., low redox potential, lower polarity and more polarizable) enable to modify the pharmacokinetic/ pharmacodynamic properties of these bioactive molecules.To leverage the therapeutic benefit of selenium, metabolically stable Se-heterocycles such as selenazoline, Selenazole and Se-substitutions are incorporated on NSAIDs scaffolds. Evaluation of the compounds for anti-proliferative activity and NF-kB and EGFR-kinase assay reveals their mechanistic aspects of anti-tumor activity.