Abstract
Redox active selenium (Se) compounds have gained substantial attention in the last decade as potential cancer therapeutic agents. Several Se compounds have shown high selectivity and sensitivity against malignant cells. The cytotoxic effects are exerted by their biologically active metabolites, with methylselenol (CH3SeH) being one of the key executors. In search of novel CH3SeH precursors, we previously synthesized a series of methylselenoesters that were active (GI50 < 10 µM at 72 h) against a panel of cancer cell lines. Herein, we refined the mechanism of action of the two lead compounds with the additional synthesis of new analogs (ethyl, pentyl, and benzyl derivatives). A novel mechanism for the programmed cell death mechanism for Se-compounds was identified. Both methylseleninic acid and the novel CH3SeH precursors induced entosis by cell detachment through downregulation of cell division control protein 42 homolog (CDC42) and its downstream effector β1-integrin (CD29). To our knowledge, this is the first time that Se compounds have been reported to induce this type of cell death and is of importance in the characterization of the anticancerogenic properties of these compounds.
Highlights
Pancreatic ductal adenocarcinoma is an extremely aggressive neoplasm and one of the cancers with the poorest prognosis, with a five-year survival of only 8% [1]
Treatment with the compounds led to a unique phenotype, characterized by changes in morphology and cell induce noteworthy cell death, with only 15% of dead cells at 72 h
We demonstrate that Methylseleninic acid (MSA) and two novel methylselenoesters induce entosis after provoking cell detachment in Panc-1 cells, revealing a new and unexplored cell death mechanism for with the compounds led to a unique phenotype, characterized by changes in morphology and cell detachment from the culture plate prior to cell death
Summary
Pancreatic ductal adenocarcinoma is an extremely aggressive neoplasm and one of the cancers with the poorest prognosis, with a five-year survival of only 8% [1]. The expression of N-cadherin, a cell-cell adhesion marker [25], showed a considerable increase after treatment with respective compounds, which explains the observed grape-like cellular clumping after detachment (Figure 3D). Treatment with z-VAD-fmk did not prevent the cellular detachment, as well as cell death, induced by these compounds, as observed by brightfield microscopy and the trypan blue exclusion assay, respectively (Supplementary Figure S1B,C), suggesting a caspase-independent mechanism. The indicate cell-in-cell formations i.e.,Compounds cells undergoing significance as
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