In pancreatic cancer cell lines exhibiting caspase-mediated apoptosis, researchers recently reported the new selenium-aspirin compound AS-10 with a cancer cell killing power 3 orders of magnitude larger than aspirin and a fair selectivity against malignant cells. Although its cytocidal activity against PC-3 and DU145 androgen receptor (AR)-negative and P53-null/mutant aggressive human prostate cancer (PCa) cell lines was also observed in the NCI-60 screen, neither its primary molecular signaling after exposure nor the potential involvement & targeting of AR & P53 pathways that are intact in early-stage prostate carcinogenesis have been studied.
The cell cycle and cell destiny responses of human LNCaP PCa cells to AS-10 exposure and upstream molecular signaling events, including histone acetylation as a recognized aspirin impact, were examined. The cells had functioning AR and intact P53. Key findings were validated using the human PCa cells 22Rv1 that were AR-positive.
They found a quick (within 5 min) enhancement of histone acetylation many hours before the reduction of AR and prostate-specific antigen (PSA, coded by KLK3 gene) in LNCaP and 22Rv1 cells, in addition to establishing AS-10’s greater cytocidal activity than aspirin against all 4 PCa cell lines. Without having an effect on the nuclear translocation or pre-existing AR protein degradation, AS-10 reduced the amounts of AR and KLK3 mRNA in LNCaP cells. As a result of prolonged exposure to AS-10, cells were primarily arrested in G1 and were subjected to caspase-mediated apoptosis without necrosis. The nontranscriptional activation of the P53 protein or Jun N-terminal Kinase cellular stress signaling, as well as the glutathione-boosting antioxidant N-acetylcysteine, all reduced the mortality caused by AS-10 in LNCaP cells. AS-10 and the histone deacetylase inhibitor SAHA worked together to reduce the amount of AR/PSA and kill LNCaP cells. A number of oncogenes, cyclin, and CDK/CKI transcriptional activities may have contributed to the cellular effects, according to RNA-seq, which also validated AR suppression at the transcriptional level.
Regardless of AR and P53 status, AS-10 increased histone acetylation as its most likely main mode of action to cause PCa cell-cycle arrest and death. However, the suppression of AR signaling by means other than classical AR antagonists may be promising when combined with androgen deprivation treatment regimens or medications that target the AR axis.