Resumen:
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-B)
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-)-stimulated NF-B nuclear translocation, DNA binding activity, and degradation of cytosolic
inhibitor of B (IB) protein. As NF-B 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.
