TY - JOUR
T1 - 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
AU - Karelia, Deepkamal N.
AU - Kim, Sangyub
AU - Pandey, Manoj K.
AU - Plano, Daniel
AU - Amin, Shantu
AU - Lu, Junxuan
AU - Sharma, Arun K.
N1 - Funding Information:
Funding: This research was funded by US National Institutes of Health National Cancer Institute grant number R21 CA234681 and R01CA172169 grant, as well as funding from Department of Pharmacology, Penn State College of Medicine, and the Penn State Cancer Institute.
Funding Information:
Acknowledgments: Authors thank the Penn State Cancer Institute Organic Synthesis Shared Resource, Genome Sciences Shared Resource Core, Flow Cytometry Shared Resource Core, and Imaging Core of the Pennsylvania State University College of Medicine. They thank Cheng Jiang, pharmacology for in depth discussions and encouragement. Cancer Institute for financial support.
Funding Information:
This research was funded by US National Institutes of Health National Cancer Institute grant number R21 CA234681 and R01CA172169 grant, as well as funding from Department of Pharmacology, Penn State College of Medicine, and the Penn State Cancer Institute. Authors thank the Penn State Cancer Institute Organic Synthesis Shared Re-source, Genome Sciences Shared Resource Core, Flow Cytometry Shared Resource Core, and Imaging Core of the Pennsylvania State University College of Medicine. They thank Cheng Jiang, pharmacology for in depth discussions and encouragement. Cancer Institute for financial support.
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/5/1
Y1 - 2021/5/1
N2 - 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.
AB - 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.
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U2 - 10.3390/ijms22094966
DO - 10.3390/ijms22094966
M3 - Article
C2 - 34067020
AN - SCOPUS:85105407081
SN - 1661-6596
VL - 22
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 9
M1 - 4966
ER -