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
| Autor: | Shantu Amin, Arun Sharma, Junxuan Lu, Manoj K. Pandey, Deepkamal N. Karelia, Daniel Plano, Sangyub Kim |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
medicine.medical_treatment pancreatic cancer Apoptosis Deoxycytidine 0302 clinical medicine RNA-Seq Biology (General) Cytotoxicity selenium Spectroscopy Chemistry NF-kappa B General Medicine Cell cycle Computer Science Applications Gene Expression Regulation Neoplastic Cytokine 030220 oncology & carcinogenesis Caspases Cytokines Inflammation Mediators Carcinoma Pancreatic Ductal Signal Transduction Programmed cell death QH301-705.5 DNA damage aspirin Adenocarcinoma Catalysis Article Inorganic Chemistry 03 medical and health sciences Pancreatic cancer Cell Line Tumor medicine Humans Physical and Theoretical Chemistry QD1-999 Molecular Biology Cell Proliferation Organic Chemistry medicine.disease G1 Phase Cell Cycle Checkpoints Gemcitabine Acetylcysteine Enzyme Activation Pancreatic Neoplasms 030104 developmental biology Cancer cell Cancer research Transcriptome |
| Zdroj: | International Journal of Molecular Sciences Volume 22 Issue 9 International Journal of Molecular Sciences, Vol 22, Iss 4966, p 4966 (2021) |
| ISSN: | 1422-0067 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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