Antitumor Activity of Gemcitabine and Oxaliplatin Is Augmented by Thymoquinone in Pancreatic Cancer

Abstract

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 Mmol/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-KB (NF-KB), Bcl-2 family, and NF-KB-dependent antiapoptotic genes (X-linked inhibitors of apoptosis, survivin, and cyclooxygenase-2). As shown previously by our laboratory, NF-KB gets activated on exposure of pancreatic cancer cells to conventional chemotherapeutic agents; interestingly, thymoquinone was able to down-regulate NF-KB 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-KB, 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 gemcitabineor oxaliplatin-induced activation of NF-KB, resulting in the chemosensitization of pancreatic tumors to conventional therapeutics. [Cancer Res 2009;69(13):5575-83]

Effects of thymoquinone against cisplatin-induced cardiac injury in rats

“…Its utilization in combined therapies may be at lower dosage, reduce the dosage of the concomitant drug optimizing efficacy and toxicity and it might also overcome the drug resistance problem 30,31 . In previous studies, it has been reported that TQ led to a decrease in mean arterial blood pressure and heart rate in hypertensive rats in a dose dependent manner isoproterenol, cyclophosphamide and doxorubicin [33][34][35] .…”

Emodin potentiates the antitumor effects of gemcitabine in pancreatic cancer cells via inhibition of nuclear factor-κB

“…The transcription nF-κB has been linked to cell proliferation, invasion, angiogenesis, metastasis and the suppression of apoptosis in pancreatic cancer (13)(14)(15)(16). Many conventional cancer chemotherapeutic agents, such as gemcitabine, vinblastine, vincristine, daunomycin, doxorubicin, campothecin, cisplatin and etoposide, have been shown to activate nF-κB (13,14,16,17).…”

“…Many conventional cancer chemotherapeutic agents, such as gemcitabine, vinblastine, vincristine, daunomycin, doxorubicin, campothecin, cisplatin and etoposide, have been shown to activate nF-κB (13,14,16,17). There are numerous lines of evidence suggesting that nF-κB plays a major role in the growth and chemo -resistance of pancreatic cancer (12,18).…”

Evaluation of Therapeutic Efficacy of Nigella sativa (Black Seed) for Treatment of Allergic Rhinitis"

“…One of the good substitutions is the use of herbal medicine and one of the ancient herbs that was used medically for many diseases was black seed extract (23) . This herb has been used for many diseases since no signs of toxicity or serious side effects were known in antiquity (24) . The role of herbal medicine in allergic rhinitis as an effective therapy has not been studied extensively (15,16,17,25) and up to our knowledge, the use of topical N.S extract in treating A.R has not been studied yet.…”