Abstract 5553: Development of novel selenium-NSAIDs as potential cancer therapeutics.

Abstract

Abstract Several non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to be effective chemopreventive agents in both pre-clinical and clinical studies on various cancer types. Here in, we developed several selenium (Se)-NSAID hybrid molecules and evaluated their efficacy as cancer therapeutics. The rationale for introducing Se into the NSAIDs is that this redox-active trace element is an essential micronutrient and a normal component of diets with chemopreventive and anticancer properties. Our recent studies have also shown that appropriately designed organoselenium compounds exhibited promising anti-tumor properties in various preclinical cancer models. We hypothesized that the rational incorporation of Se into NSAIDs should enhance their anti-cancer properties and therefore, we synthesized 16 novel Se-NSAID hybrid agents designed by incorporating Se moieties into the structures of aspirin, ibuprofen, and naproxen. In the first phase, a selenocyanate moiety was incorporated to these NSAIDs and screened for their cytotoxicity in various cancer cell lines. The cell viability results at 24 and 48 h showed that the introduction of this Se functionality on aspirin scaffold achieved a dramatic increase in the activity as compared to aspirin, as well as other NSAIDs or their Se hybrids. Thus, we continued optimization of aspirin with a variety of Se moieties, such as selenides and selenomethyl functionalities. Most of these compounds reduced cell viability in a dose dependent manner, while aspirin had no significant effect. Based on these studies we identified two Se-aspirin hybrid compounds; ASD-43, having a selenide functionality and ASD-49, with a selenocyanate functionality, as the most potent compounds for further development. The IC50 values after 48 h treatment in HCT116 cells were 2.5μM and 1.0 μM and in MiaPaCa-2 cells were 5.0 μM and 2.5 μM for ASD-43 and ASD-49, respectively. To further establish the cytotoxic potential of these compounds, an esterase staining (live and dead) assay was performed in colon (HCT116) and pancreatic (MiaPaCa-2) cancer cells. Treatment of ASD-43 and ASD-49 reduced cell viabilities dose dependently in both HCT116 and MiaPaCa-2 cells, while aspirin had no significant effects. In addition, both these compounds induced caspase-mediated PARP cleavage as early as 24 h in HCT116 cells. In conclusion, new Se-NSAID hybrid agents have been developed which showed a solid potential to be effective cancer therapeutics in our initial studies. Detailed results of these investigations will be presented. Citation Format: Daniel Plano, Deepkamal Karelia, Manoj Pandey, Shantu Amin, Arun K. Sharma. Development of novel selenium-NSAIDs as potential cancer therapeutics. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5553. doi:10.1158/1538-7445.AM2013-5553