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1157
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could be useful for combination therapy using radiation,
which of course requires further in-depth investigations. A
broad spectrum of cell cycle genes trigger the disruption of
the cell membrane integrity in response to stress condition
elicited by cell cycle arrest. This can be viewed as one
speculative reason for the differential trend between cell
viability and cell cycle progression, as noted with the
analogs in the present study.
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Although complete understanding of the underlying
apoptosis-inducing mechanism of these novel analogs is
required, the initial findings reported here are encouraging,
especially the chemosensitizing effects of these analogs to
conventional agents that are not very effective in the
treatment of PC. Our findings on chemoresistant
MiaPaCa-2 cells clearly suggest that these compounds
may hold promise for combination therapy toward better
treatment outcome of patients diagnosed with PC. Inter-
estingly, our preliminary data suggest that TQ-2G is non-
toxic in SCID mice at doses up to 50 mg/kg when
administered through i.v. route and a dose up to 700 mg/
kg when administered orally by gavage, which suggests that
this analog could indeed be useful in combination therapy
without added toxicity when combined with conventional
therapeutics such as gemcitabine or oxaliplatin. Of added
interest, the synthesized analogs described closely mirror
Lipinski’s Rule of Five.
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Thymoquinone induces apoptosis through activation of caspase-
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In conclusion, we presented preliminary evidence for
novel synthesis of TQ analogs with biological activity that is
better than the parental TQ without systemic toxicity; thus,
we believe that these and other novel analogs of TQ, could
serve as promising agents for better treatment outcome of
patients diagnosed with pancreatic cancer.
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Thymoquinone inhibits tumor angiogenesis and tumor growth
through suppressing AKT and extracellular signal-regulated
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ACKNOWLEDGEMENTS
The authors express their sincere appreciation to Ms.
Christine Wojewoda for her editorial assistance. Grant
support from the National Institutes of Health RO1CA109389
(RM Mohammad) and NIH R01CA083695, R01CA131151,
and R01CA132794 awarded to FHS is gratefully acknowl-
edged. The authors also acknowledge the financial contribu-
tion of Guido Foundation.
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