Pharmaceutical Research

, Volume 27, Issue 6, pp 1146–1158 | Cite as

Structure-Activity Studies on Therapeutic Potential of Thymoquinone Analogs in Pancreatic Cancer

  • Sanjeev Banerjee
  • Asfar S. Azmi
  • Subhash Padhye
  • Marjit W. Singh
  • Jubaraj B. Baruah
  • Philip A. Philip
  • Fazlul H. Sarkar
  • Ramzi M. MohammadEmail author
Research Paper



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.


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.


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.


From our results, we conclude that three of our novel TQ analogs warrant further investigation against PC, especially in combination with conventional chemotherapeutic agents.


apoptosis pancreatic cancer thymoquinone thymoquinone analogs 



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.


  1. 1.
    Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin. 2009;59:225–49.CrossRefPubMedGoogle Scholar
  2. 2.
    Lage H, Dietel M. Multiple mechanisms confer different drug-resistant phenotypes in pancreatic carcinoma cells. J Cancer Res Clin Oncol. 2002;128:349–57.CrossRefPubMedGoogle Scholar
  3. 3.
    Bardeesy N, DePinho RA. Pancreatic cancer biology and genetics. Nat Rev Cancer. 2002;2:897–909.CrossRefPubMedGoogle Scholar
  4. 4.
    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.CrossRefPubMedGoogle Scholar
  5. 5.
    Arlt A, Schafer H. NFkappaB-dependent chemoresistance in solid tumors. Int J Clin Pharmacol Ther. 2002;40:336–47.PubMedGoogle Scholar
  6. 6.
    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.CrossRefPubMedGoogle Scholar
  7. 7.
    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.PubMedGoogle Scholar
  8. 8.
    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.PubMedGoogle Scholar
  9. 9.
    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.PubMedGoogle Scholar
  10. 10.
    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.PubMedGoogle Scholar
  11. 11.
    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.PubMedCrossRefGoogle Scholar
  12. 12.
    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.PubMedGoogle Scholar
  13. 13.
    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.CrossRefPubMedGoogle Scholar
  14. 14.
    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.CrossRefPubMedGoogle Scholar
  15. 15.
    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.CrossRefPubMedGoogle Scholar
  16. 16.
    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.CrossRefPubMedGoogle Scholar
  17. 17.
    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.PubMedGoogle Scholar
  18. 18.
    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.CrossRefPubMedGoogle Scholar
  19. 19.
    Khan MN, Lee YS. Cyclooxygenase inhibitors: Scope of their use and development in cancer chemotherapy. Med Res Rev. 2009.Google Scholar
  20. 20.
    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.CrossRefPubMedGoogle Scholar
  21. 21.
    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.CrossRefPubMedGoogle Scholar
  22. 22.
    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.PubMedGoogle Scholar
  23. 23.
    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.PubMedGoogle Scholar
  24. 24.
    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.PubMedGoogle Scholar
  25. 25.
    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.CrossRefPubMedGoogle Scholar
  26. 26.
    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.CrossRefPubMedGoogle Scholar
  27. 27.
    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.PubMedGoogle Scholar
  28. 28.
    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.CrossRefPubMedGoogle Scholar
  29. 29.
    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.PubMedGoogle Scholar
  30. 30.
    Sarkar FH, Li Y. NF-kappaB: a potential target for cancer chemoprevention and therapy. Front Biosci. 2008;13:2950–9.CrossRefPubMedGoogle Scholar
  31. 31.
    Sarkar FH, Li YW. Targeting multiple signal pathways by chemopreventive agents for cancer prevention and therapy. Acta Pharmacol Sin. 2007;28:1305–15.CrossRefPubMedGoogle Scholar
  32. 32.
    Sarkar FH, Banerjee S, Li Y. Pancreatic cancer: pathogenesis, prevention and treatment. Toxicol Appl Pharmacol. 2007;224:326–36.CrossRefPubMedGoogle Scholar
  33. 33.
    Sarkar FH, Li Y. Using chemopreventive agents to enhance the efficacy of cancer therapy. Cancer Res. 2006;66:3347–50.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Sanjeev Banerjee
    • 1
  • Asfar S. Azmi
    • 1
  • Subhash Padhye
    • 4
  • Marjit W. Singh
    • 3
  • Jubaraj B. Baruah
    • 3
  • Philip A. Philip
    • 2
  • Fazlul H. Sarkar
    • 1
  • Ramzi M. Mohammad
    • 2
    Email author
  1. 1.Department of Pathology Barbara Ann Karmanos Cancer InstituteWayne State University School of MedicineDetroitUSA
  2. 2.Division of Hematology and Oncology, Barbara Ann Karmanos Cancer InstituteWayne State University School of MedicineDetroitUSA
  3. 3.Department of ChemistryIndian Institute of TechnologyGuwahatiIndia
  4. 4.D.Y.Patil UniversityPuneIndia

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