Previous studies have shown biological activity of
thymoquinone, an active compound extracted from Nigella sativa, in
pancreatic cancer cells; however, preclinical animal studies are lacking. Here, we report, for the first time, the chemosensitizing effect of
thymoquinone to conventional chemotherapeutic agents both in vitro and in vivo using an orthotopic model of
pancreatic cancer. In vitro studies revealed that preexposure of cells with
thymoquinone (25 mumol/L) for 48 h followed by
gemcitabine or
oxaliplatin resulted in 60% to 80% growth inhibition compared with 15% to 25% when
gemcitabine or
oxaliplatin was used alone. Moreover, we found that
thymoquinone could potentiate the killing of
pancreatic cancer cells induced by chemotherapeutic agents by down-regulation of
nuclear factor-kappaB (
NF-kappaB), Bcl-2 family, and
NF-kappaB-dependent antiapoptotic genes (X-linked inhibitors of apoptosis,
survivin, and
cyclooxygenase-2). As shown previously by our laboratory,
NF-kappaB gets activated on exposure of
pancreatic cancer cells to conventional chemotherapeutic agents; interestingly,
thymoquinone was able to down-regulate
NF-kappaB in vitro, resulting in chemosensitization. In addition to in vitro results, here we show for the first time, that
thymoquinone in combination with
gemcitabine and/or
oxaliplatin is much more effective as an
antitumor agent compared with either agent alone. Most importantly, our data also showed that a specific target, such as
NF-kappaB, was inactivated in animal
tumors pretreated with
thymoquinone followed by
gemcitabine and/or
oxaliplatin. These results provide strong in vivo molecular evidence in support of our hypothesis that
thymoquinone could abrogate
gemcitabine- or
oxaliplatin-induced activation of
NF-kappaB, resulting in the chemosensitization of pancreatic
tumors to conventional
therapeutics.