Inflammation plays an important role in tumor growth promotion and has been linked to several human cancers. Evidences have demonstrated that inflammation has a high correlation with pancreatic cancer (PC) growth and promotion. An important mediator of inflammatory process is Cyclooxygenase 2 (COX-2) protein, which has been shown to be over-expressed in PC. Another major pathway which is crucial for inflammatory responses, cell proliferation, and resistance to apoptosis is the nuclear factor κB (NF-κB) pathway. It has been demonstrated that NF-κB pathway is responsible for drug resistance in PC. Aspirin, a well-known non-steroidal anti-inflammatory drug (NSAID), has been shown to have anti-cancer effects against PC. The mechanism of action of aspirin against PC is partially dependent on COX inhibition, as well as COX independent mechanism. Through extensive structure-activity relationship studies on Se-NSAID compounds, we have recently identified two Se-Aspirin compounds, ASD-43 and ASD-49, designed by incorporating selenium (Se) into salicylic acid structure, rendering it lethal to cancer cells. Previously, we had reported that Se-aspirin hybrid compounds were effective in different cancers, including PC. In this study we sought to evaluate the mechanism of action of these compounds in inhibiting the growth of PC. Since aspirin induces its effect partially by inhibiting COX, we hypothesized that these agents (ASD-43 and ASD-49) showed their anti-cancer activity by potently inhibiting COX activity as well as by modulating the inflammatory NF-κB pathway. Our studies, in Panc-1 cells, have shown that both ASD-43 and ASD-49 inhibited the degradation of IκB-alpha, which inhibits NF-κB from going into the nucleus, in presence of tumor necrosis factor (TNF). Upon treatment with ASD-43 and ASD-49, NF-κB regulated proteins like survivin and Bcl-xL expression was down regulated. Furthermore, a dose dependent induction of apoptosis in these cells was detected by activation of caspase-3 and PARP cleavage. Taken together, these results suggest that both ASD-43 and ASD-49 may represent potentially promising therapeutic agents for PC that induce apoptosis via the inhibition of COX and NF-κB pathways. Detailed investigations regarding the efficacy and mechanism of action of these compounds will be presented.

Citation Format: Deepkamal N. Karelia, Manoj K. Pandey, Daniel Plano, Shantu Amin, Arun K. Sharma. Novel aspirin based selenium compounds as therapy against pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 814. doi:10.1158/1538-7445.AM2014-814