ABSTRACT
Purpose
Pancreatic cancer (PC) is one of the deadliest of all tumors. Previously, we were the first to show that Thymoquinone (TQ) derived from black seed (Nigella sativa) oil has anti-tumor activity against PC. However, the concentration of TQ required was considered to be high to show this efficacy. Therefore, novel analogs of TQ with lower IC50 are highly desirable.
Methods
We have synthesized a series of 27 new analogs of TQ by modifications at the carbonyl sites or the benzenoid sites using single pot synthesis and tested their biological activity in PC cells.
Results
Among these compounds, TQ-2G, TQ-4A1 and TQ-5A1 (patent pending) were found to be more potent than TQ in terms of inhibition of cell growth, induction of apoptosis and modulation of transcription factor-NF-κB. We also found that our novel analogs were able to sensitize gemcitabine and oxaliplatin-induced apoptosis in MiaPaCa-2 (gemcitabine resistant) PC cells, which was associated with down-regulation of Bcl-2, Bcl-xL, survivin, XIAP, COX-2 and the associated Prostaglandin E2.
Conclusion
From our results, we conclude that three of our novel TQ analogs warrant further investigation against PC, especially in combination with conventional chemotherapeutic agents.
Similar content being viewed by others
REFERENCES
Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin. 2009;59:225–49.
Lage H, Dietel M. Multiple mechanisms confer different drug-resistant phenotypes in pancreatic carcinoma cells. J Cancer Res Clin Oncol. 2002;128:349–57.
Bardeesy N, DePinho RA. Pancreatic cancer biology and genetics. Nat Rev Cancer. 2002;2:897–909.
Hu X, Xuan Y. Bypassing cancer drug resistance by activating multiple death pathways–a proposal from the study of circumventing cancer drug resistance by induction of necroptosis. Cancer Lett. 2008;259:127–37.
Arlt A, Schafer H. NFkappaB-dependent chemoresistance in solid tumors. Int J Clin Pharmacol Ther. 2002;40:336–47.
Banerjee S, Kaseb AO, Wang Z, Kong D, Mohammad M, Padhye S et al. Antitumor activity of gemcitabine and oxaliplatin is augmented by thymoquinone in pancreatic cancer. Cancer Res. 2009;69:5575–83.
Padhye S, Banerjee S, Ahmad A, Mohammad R, Sarkar FH. From here to eternity—the secret of Pharaohs: therapeutic potential of black cumin seeds and beyond. Cancer Ther. 2008;6:495–510.
Rooney S, Ryan MF. Effects of alpha-hederin and thymoquinone, constituents of Nigella sativa, on human cancer cell lines. Anticancer Res. 2005;25:2199–204.
Shoieb AM, Elgayyar M, Dudrick PS, Bell JL, Tithof PK. In vitro inhibition of growth and induction of apoptosis in cancer cell lines by thymoquinone. Int J Oncol. 2003;22:107–13.
Gali-Muhtasib H, ab-Assaf M, Boltze C, Al-Hmaira J, Hartig R, Roessner A et al. Thymoquinone extracted from black seed triggers apoptotic cell death in human colorectal cancer cells via a p53-dependent mechanism. Int J Oncol. 2004;25:857–66.
Roepke M, Diestel A, Bajbouj K, Walluscheck D, Schonfeld P, Roessner A et al. Lack of p53 augments thymoquinone-induced apoptosis and caspase activation in human osteosarcoma cells. Cancer Biol Ther. 2007;6:160–9.
Wilson-Simpson F, Vance S, Benghuzzi H. Physiological responses of ES-2 ovarian cell line following administration of epigallocatechin-3-gallate (EGCG), thymoquinone (TQ), and selenium (SE). Biomed Sci Instrum. 2007;43:378–83.
El-Mahdy MA, Zhu Q, Wang QE, Wani G, Wani AA. Thymoquinone induces apoptosis through activation of caspase-8 and mitochondrial events in p53-null myeloblastic leukemia HL-60 cells. Int J Cancer. 2005;117:409–17.
Kaseb AO, Chinnakannu K, Chen D, Sivanandam A, Tejwani S, Menon M et al. Androgen receptor and E2F-1 targeted thymoquinone therapy for hormone-refractory prostate cancer. Cancer Res. 2007;67:7782–8.
Yi T, Cho SG, Yi Z, Pang X, Rodriguez M, Wang Y et al. Thymoquinone inhibits tumor angiogenesis and tumor growth through suppressing AKT and extracellular signal-regulated kinase signaling pathways. Mol Cancer Ther. 2008;7:1789–96.
Sethi G, Ahn KS, Aggarwal BB. Targeting nuclear factor-kappa B activation pathway by thymoquinone: role in suppression of antiapoptotic gene products and enhancement of apoptosis. Mol Cancer Res. 2008;6:1059–70.
Bauer L, Venz S, Junker H, Brandt R, Radons J. Nicotinamide phosphoribosyltransferase and prostaglandin H2 synthase 2 are up-regulated in human pancreatic adenocarcinoma cells after stimulation with interleukin-1. Int J Oncol. 2009;35:97–107.
Angst E, Reber HA, Hines OJ, Eibl G. Mononuclear cell-derived interleukin-1 beta confers chemoresistance in pancreatic cancer cells by upregulation of cyclooxygenase-2. Surgery. 2008;144:57–65.
Khan MN, Lee YS. Cyclooxygenase inhibitors: Scope of their use and development in cancer chemotherapy. Med Res Rev. 2009.
Yip-Schneider MT, Barnard DS, Billings SD, Cheng L, Heilman DK, Lin A et al. Cyclooxygenase-2 expression in human pancreatic adenocarcinomas. Carcinogenesis. 2000;21:139–46.
Ali S, El-Rayes BF, Sarkar FH, Philip PA. Simultaneous targeting of the epidermal growth factor receptor and cyclooxygenase-2 pathways for pancreatic cancer therapy. Mol Cancer Ther. 2005;4:1943–51.
Colby JK, Klein RD, McArthur MJ, Conti CJ, Kiguchi K, Kawamoto T et al. Progressive metaplastic and dysplastic changes in mouse pancreas induced by cyclooxygenase-2 overexpression. Neoplasia. 2008;10:782–96.
Zatelli MC, Mole D, Tagliati F, Minoia M, Ambrosio MR, Uberti ED. Cyclo-oxygenase 2 modulates chemoresistance in breast cancer cells involving NF-kappaB. Cell Oncol. 2009;31:457–65.
Robertson FM, Mallery SR, Bergdall-Costell VK, Cheng M, Pei P, Prosperi JR et al. Cyclooxygenase-2 directly induces MCF-7 breast tumor cells to develop into exponentially growing, highly angiogenic and regionally invasive human ductal carcinoma xenografts. Anticancer Res. 2007;27:719–27.
Stasinopoulos I, O’Brien DR, Wildes F, Glunde K, Bhujwalla ZM. Silencing of cyclooxygenase-2 inhibits metastasis and delays tumor onset of poorly differentiated metastatic breast cancer cells. Mol Cancer Res. 2007;5:435–42.
Nassar A, Radhakrishnan A, Cabrero IA, Cotsonis G, Cohen C. COX-2 expression in invasive breast cancer: correlation with prognostic parameters and outcome. Appl Immunohistochem Mol Morphol. 2007;15:255–9.
Singh B, Berry JA, Shoher A, Ramakrishnan V, Lucci A. COX-2 overexpression increases motility and invasion of breast cancer cells. Int J Oncol. 2005;26:1393–9.
Valsecchi ME, Pomerantz SC, Jaslow R, Tester W. Reduced risk of bone metastasis for patients with breast cancer who use COX-2 inhibitors. Clin Breast Cancer. 2009;9:225–30.
Simeone AM, Nieves-Alicea R, McMurtry VC, Colella S, Krahe R, Tari AM. Cyclooxygenase-2 uses the protein kinase C/ interleukin-8/urokinase-type plasminogen activator pathway to increase the invasiveness of breast cancer cells. Int J Oncol. 2007;30:785–92.
Sarkar FH, Li Y. NF-kappaB: a potential target for cancer chemoprevention and therapy. Front Biosci. 2008;13:2950–9.
Sarkar FH, Li YW. Targeting multiple signal pathways by chemopreventive agents for cancer prevention and therapy. Acta Pharmacol Sin. 2007;28:1305–15.
Sarkar FH, Banerjee S, Li Y. Pancreatic cancer: pathogenesis, prevention and treatment. Toxicol Appl Pharmacol. 2007;224:326–36.
Sarkar FH, Li Y. Using chemopreventive agents to enhance the efficacy of cancer therapy. Cancer Res. 2006;66:3347–50.
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 acknowledged. The authors also acknowledge the financial contribution of Guido Foundation.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Banerjee, S., Azmi, A.S., Padhye, S. et al. Structure-Activity Studies on Therapeutic Potential of Thymoquinone Analogs in Pancreatic Cancer. Pharm Res 27, 1146–1158 (2010). https://doi.org/10.1007/s11095-010-0145-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11095-010-0145-3