Abstract 1253: Dissecting the signaling cascades involved in growth inhibition and apoptosis of prostate cancer cells exposed to a novel bis-aspirinyl selenazolidine AS-10
Authors: Karelia Deepkamal N. , Kim Sangyub , Ramisetti Srinivasa , Jiang Cheng , Amin Shantu , Sharma Arun K. , Lu Junxuan 
Published: August 2018

Aspirin has been recommended for 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 focused on enhancing its anticancer activity by incorporation of selenium, we identified bis-aspirinyl selenazolidine (AS-10) as a novel promising lead compound against different cancer cell types in the NCI-60 cancer cell line panel, including prostate cancer (PCa) (e.g., EC50 in range of 1.7 to 2.5 μM for PCa cells compared with aspirin in the millimolar range). We have earlier found that AS-10 inhibited androgen receptor (AR) signaling in LNCaP cells and induced caspase-mediated apoptosis along with activation of DNA damage response (DDR) proteins such as P53 and its canonical target P21Cip1 and the DNA double strand break marker protein phospho-H2A.X. The objective of the present work is to analyze the signaling pathways underlying the growth arrest and apoptotic effects of AS-10. In time course studies, AS-10 treatment decreased the expression of AR and its downstream target prostate specific antigen (PSA) as early as 3 h in LNCaP cells. AS-10 inhibited the progression of LNCaP cells from G1 into S phase, far ahead of an increase in apoptotic sub-G0/G1 cells. At the protein level, AS-10 treatment decreased the expression of proliferative oncoprotein c-Myc and anti-apoptotic molecules such as Mcl-1, Bcl-xL and survivin. Temporally, AS-10 increased P53 and P21Cip1 expression and PARP cleavage ahead of increased phospho-H2A.X which might simply mark apoptotically fragmented DNA. By si-RNA transfection, knocking down of P53 or P21Cip1 in LNCaP cells increased cell death induced by AS-10, indicating an anti-apoptotic role of this regulator-target pair. These data suggest that suppression of AR signaling and prosurvival proteins by AS-10 may contribute to cell cycle arrest and apoptosis, subject to P53 status.

Additionally, aspirin has been known to acetylate histones and other proteins. Because AS-10 contains two aspirin moieties, we hypothesize that the combination of AS-10 with a histone deacetylates (HDAC) inhibitor (Vorinostat) may further increase overall acetylation and synergize to induce PCa cell death. Our results demonstrate that the combination of AS-10 and Vorinostat induced more than additive cell death response.

In summary, AS-10 represents a promising potential chemopreventive agent for prostate carcinogenesis, alone or in combination with other drugs, through multiple molecular targets and cellular pathways and merits efficacy assessment in animal models.

Citation Format: Deepkamal N. Karelia, Sangyub Kim, Srinivasa Ramisetti, Cheng Jiang, Shantu Amin, Arun K. Sharma, Junxuan Lu. Dissecting the signaling cascades involved in growth inhibition and apoptosis of prostate cancer cells exposed to a novel bis-aspirinyl selenazolidine AS-10 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1253.