Abstract 2237: Novel selenium-containing aspirin molecule AS-10 suppresses androgen receptor signaling and induces apoptosis of LNCap prostate cancer cells
Authors: Deepkamal N. Karelia, Sangyub Kim, Srinivasa Ramisetti, Cheng Jiang, Shantu Amin, Arun K. Sharma, Junxuan Lu
Journal: Cancer Research (2017)

Abstract Aspirin as the best known low cost Non-Steroidal Anti-inflammatory drug (NSAID) has been associated with lowering risk of colorectal cancer, in addition to its cardiovascular health benefit at low dose (baby Aspirin) and over-the-counter pain medication. Through an innovative research program aiming at enhancing the bioactivities of NSAIDs by incorporation of selenium, we have discovered AS-10 as a novel Aspirin-selenium compound with promising anti-cancer drug-like properties in terms of potency enhancement (at least 3 orders of magnitude compared to Aspirin), selective cytotoxicity against cancer cells including majority of NCI-60 panel, while sparing normal moue embryonic fibroblasts in cell culture screening assays. Preliminary toxicology study in mice had shown a wide safety margin. Extensive structure-activity relationship investigation suggested a novel structural basis, instead of releasable selenium, that accounted for the striking potency. To investigate the potential chemopreventive attributes of AS-10 against prostate carcinogenesis, we selected LNCaP cells (wild type p53, functional androgen receptor, AR) to examine the growth suppression and apoptosis responses in cell culture. The rationale for choosing LNCaP cell line as target cells rests in the fact that precancerous prostatic lesions that are the intended targets of chemoprevention as well as early stage prostate cancer retain wild type p53 and they are critically dependent on AR signaling for survival. Our results show that cell viability (MTT) test detected a potent growth inhibition of LNCaP cells in a time and concentration dependent manner, with an EC50 in range of 1.7 to 2.5 μM range compared with Aspirin in the millimolar range. Western blot analysis of AS-10 treated LNCaP cells showed decreased protein level of AR and its best known downstream target prostate specific antigen (PSA) in a concentration-dependent manner. In addition, AS-10 treatment led to increased Annexin V staining, caspase 3/7 activity, and PARP cleavage, all indicators of caspase-mediated apoptosis. Furthermore, AS-10 treatment increased the expression of p53-DNA damage response (DDR) proteins such as p21 (canonical target of p53) and p-H2A.X (a marker for DNA strand breaks). Given that our earlier work with pancreatic cancer cells has indicated a rapid induction of reactive oxygen species (ROS) by AS-10 exposure, we hypothesize that ROS generation may be involved in LNCaP cells to trigger the DDR and apoptosis responses. In summary, our findings suggest AS-10 as a potential chemopreventive agent for prostate carcinogenesis. Citation Format: Deepkamal N. Karelia, Sangyub Kim, Srinivasa Ramisetti, Cheng Jiang, Shantu Amin, Arun K. Sharma, Junxuan Lu. Novel selenium-containing aspirin molecule AS-10 suppresses androgen receptor signaling and induces apoptosis of LNCap prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2237. doi:10.1158/1538-7445.AM2017-2237