Novel Seleno-Aspirinyl Compound AS-10 Induces Apoptosis, G1 Arrest of Pancreatic Ductal Adenocarcinoma Cells, Inhibits Their NF-κB Signaling, and Synergizes with Gemcitabine Cytotoxicity.

Abstract

Current available therapies for pancreatic ductal adenocarcinoma (PDAC) provide minimal overall survival benefits and cause severe adverse effects. We have identified a novel molecule AS-10, a selenazolidine-bis-aspirinyl derivative, that was two to three orders of magnitude more potent than aspirin and at least one to two orders of magnitude more potent than gemcitabine in inhibiting PDAC cancer cell growth/viability against three PDAC cell lines while sparing mouse embryonic fibroblasts in the same exposure range. In Panc-1 cells, AS-10 induced apoptosis without necrosis, principally through caspase-3/7 cascade and reactive oxygen species, in addition to an induction of G1 cell cycle block. Transcriptomic profiling with RNA-seq indicated the top responses to AS-10 exposure as CDKN1A (P21Cip1), CCND1, and nuclear transcription factor-kappa B (NF-κB) complex and the top functions as cell cycle, cell death, and survival without inducing the DNA damage gene signature. AS-10 pretreatment (6 h) decreased cytokine tumor necrosis factor-alpha (TNF-α)-stimulated NF-κB nuclear translocation, DNA binding activity, and degradation of cytosolic inhibitor of κB (IκB) protein. As NF-κB activation in PDAC cells confers resistance to gemcitabine, the AS-10 combination with gemcitabine increased the in vitro cytotoxicity more than the additivity of both compounds. Overall, our results suggest AS-10 may be a promising drug lead for PDAC, both as a single agent and in combination therapy.

• Authors: Deepkamal N Karelia, Sangyub Kim, Manoj K Pandey, Daniel Plano, Shantu Amin, Junxuan Lu, Arun K Sharma
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 9 (May 07 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 34067020 (Publication Type: Journal Article)

Chemical References

• Cytokines
• Inflammation Mediators
• NF-kappa B
• Deoxycytidine
• Caspases
• Aspirin
• Acetylcysteine
• Gemcitabine

Topics

• Acetylcysteine (pharmacology)
• Adenocarcinoma (genetics, pathology)
• Apoptosis (drug effects, genetics)
• Aspirin (chemistry, pharmacology)
• Carcinoma, Pancreatic Ductal (genetics, pathology)
• Caspases (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cytokines (metabolism)
• Deoxycytidine (analogs & derivatives, pharmacology)
• Enzyme Activation (drug effects)
• G1 Phase Cell Cycle Checkpoints (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Inflammation Mediators (metabolism)
• NF-kappa B (metabolism)
• Pancreatic Neoplasms (genetics, pathology)
• Signal Transduction (drug effects)
• Transcriptome (drug effects, genetics)
• Gemcitabine
• Pancreatic Neoplasms