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Anticancer Action of Thymoquinone

  • Arshad H. RahmaniEmail author
Chapter

Abstract

Thymoquinone (TQ) is a biologically active compound found in the Nigella sativa and extensively studied over the decades for its implications in diseases management without promoting the adverse side effects. An extensive number of researches have been performed to evaluate the efficacy of TQ in killing of cancer cells through modulating several biological activities, which play a vital role in the pathogenesis of cancer. Moreover, TQ shows an important role in the induction of apoptosis as well as cell cycle arrest in cancerous cells through the upregulation of PTEN gene and cyclin-dependent kinase inhibitor. A novel molecular target of TQ against numerous cancerous cells or inhibition of cancer growth is the modulation of protein kinase, nuclear factor kappa B, angiogenesis and tumorigenesis. Although numerous studies based on animal model and laboratory research have been performed to assess the potentiality of TQ in cancer prevention, chemopreventive role of TQ in humans is still unexplored. However, detailed and appropriate studies are needed to authenticate the role of TQ as a future drug therapy in the management of cancer.

References

  1. Abdelfadil E, Cheng YH, Bau DT et al (2013) Thymoquinone induces apoptosis in oral cancer cells through p38β inhibition. Am J Chin Med 41(3):683–696CrossRefGoogle Scholar
  2. AbuKhader MM (2012) The effect of route of administration in thymoquinone toxicity in male and female rats. Indian J Pharm Sci 74(3):195–200CrossRefGoogle Scholar
  3. Acharya BR, Chatterjee A, Ganguli A et al (2014) Thymoquinone inhibits microtubule polymerization by tubulin binding and causes mitotic arrest following apoptosis in A549 cells. Biochimie 97:78–91CrossRefGoogle Scholar
  4. Ahmad A, Khan RM, Alkharfy KM et al (2015) Thymoquinone on the pharmacokinetics and pharmacodynamics of glibenclamide in a rat model. Nat Prod Commun 10(8):1395–1398PubMedGoogle Scholar
  5. Al-Ali A, Alkhawajah AA, Randhawa MA et al (2008) Oral and intraperitoneal LD50 of thymoquinone, an active principle of Nigella sativa, in mice and rats. J Ayub Med Coll Abbottabad 20:25–27PubMedGoogle Scholar
  6. Al-Amri AM, Bamosa AO (2009) Phase I safety and clinical activity study of thymoquinone in patients with advanced refractory malignant disease. Shiraz E-Med J 10(3):107–111Google Scholar
  7. Alhosin M, Ibrahim A, Boukhari A et al (2012) Anti-neoplastic agent thymoquinone induces degradation of alpha and beta tubulin proteins in human cancer cells without affecting their level in normal human fibroblasts. Investig New Drugs 30:1813–1819CrossRefGoogle Scholar
  8. Ali Salim LZ, Othman R, Abdulla MA et al (2014) Thymoquinone inhibits murine leukemia WEHI-3 cells in vivo and in vitro. PLoS One 9(12):e115340CrossRefGoogle Scholar
  9. Arafa el SA, Zhu Q, Shah ZI et al (2011) Thymoquinone up-regulates PTEN expression and induces apoptosis in doxorubicin-resistant human breast cancer cells. Mutat Res 706:28–35CrossRefGoogle Scholar
  10. Ashour AE, Abd-Allah AR, Korashy HM et al (2014) Thymoquinone suppression of the human hepatocellular carcinoma cell growth involves inhibition of IL-8 expression, elevated levels of TRAIL receptors, oxidative stress and apoptosis. Mol Cell Biochem 389:85–98CrossRefGoogle Scholar
  11. Attoub S, Sperandio O, Raza H et al (2013) Thymoquinone as an anticancer agent: evidence from inhibition of cancer cells viability and invasion in vitro and tumor growth in vivo. Fundam Clin Pharmacol 27(5):557–569CrossRefGoogle Scholar
  12. Badary O, Al-Shabanah O, Nagi M et al (1998) Acute and subchronic toxicity of thymoquinone in mice. Drug Dev Res 44:56–61CrossRefGoogle Scholar
  13. Badr G, Mohany M, Abu-Tarboush F (2011) Thymoquinone decreases F-actin polymerization and the proliferation of human multiple myeloma cells by suppressing STAT3 phosphorylation and Bcl2/Bcl-XL expression. Lipids Health Dis 10:236CrossRefGoogle Scholar
  14. Banerjee S, Kaseb AO, Wang Z et al (2009) Antitumor activity of gemcitabine and oxaliplatin is augmented by thymoquinone in pancreatic cancer. Cancer Res 69(13):5575–5583CrossRefGoogle Scholar
  15. Bhattacharya S, Ahir M, Patra P et al (2015) PEGylated-thymoquinone-nanoparticle mediated retardation of breast cancer cell migration by deregulation of cytoskeletal actin polymerization through miR-34a. Biomaterials 51:91–107CrossRefGoogle Scholar
  16. Boyle P, Levin BE (eds) (2008) World cancer report. IARC. IARC Press, LyonGoogle Scholar
  17. Chehl N, Chipitsyna G, Gong Q et al (2009) Anti-inflammatory effects of the Nigella sativa seed extract, thymoquinone, in pancreatic cancer cells. HPB (Oxford) 11(5):373–381CrossRefGoogle Scholar
  18. Chu SC, Hsieh YS, Yu CC et al (2014) Thymoquinone induces cell death in human squamous carcinoma cells via caspase activation-dependent apoptosis and LC3-II activation-dependent autophagy. PLoS One 9:e101579CrossRefGoogle Scholar
  19. Collins K, Mitchell JR (2002) Telomerase in the human organism. Oncogene 21(4):564–579CrossRefGoogle Scholar
  20. Das S, Dey KK, Dey G et al (2012) Antineoplastic and apoptotic potential of traditional medicines thymoquinone and diosgenin in squamous cell carcinoma. PLoS One 7:e46641CrossRefGoogle Scholar
  21. Dastjerdi D, Mehdiabady E, Iranpour F et al (2016) Effect of thymoquinone on P53 gene expression and consequence apoptosis in breast cancer cell line. Int J preventative med 7(1):66–71CrossRefGoogle Scholar
  22. Di Cristofano A, Pandolfi PP (2000) The multiple roles of PTEN in tumor suppression. Cell 100:387–390CrossRefGoogle Scholar
  23. Dirican A, Erten C, Atmaca H et al (2014) Enhanced cytotoxicity and apoptosis by thymoquinone in combination with zoledronic acid in hormone- and drug-resistant prostate cancer cell lines. Journal of BUON: official journal of the Balkan Union of. Oncology 19(4):1055–1061Google Scholar
  24. El Mezayen R, El Gazzar M, Nicolls MR et al (2006) Effect of thymoquinone on cyclooxygenase expression and prostaglandin production in a mouse model of allergic airway inflammation. Immunol Lett 106:72–81CrossRefGoogle Scholar
  25. Elbarbry F, Ragheb A, Marfleet T et al (2012) Modulation of hepatic drug metabolizing enzymes by dietary doses of thymoquinone in female New Zealand white rabbits. Phytother Res 26(11):1726–1730CrossRefGoogle Scholar
  26. ElKhoely A, Hafez HF, Ashmawy AM et al (2015) Chemopreventive and therapeutic potentials of thymoquinone in HepG2 cells: mechanistic perspectives. J Nat Med 69(3):313–323CrossRefGoogle Scholar
  27. El-Mahdy MA, Zhu Q, Wang QE et al (2005) Thymoquinone induces apoptosis through activation of caspase-8 and mitochondrial events in p53-null myeloblastic leukemia HL-60 cells. Int J Cancer 117(3):409–417CrossRefGoogle Scholar
  28. El-Najjar N, Chatila M, Moukadem H et al (2010) Reactive oxygen species mediate thymoquinone-induced apoptosis and activate ERK and JNK signaling. Apoptosis 15(2):183–195CrossRefGoogle Scholar
  29. El-Sheikh AA, Morsy MA, Abdalla AM et al (2015) Mechanisms of thymoquinone hepatorenal protection in methotrexateinduced toxicity in rats. Mediat Inflamm 2015:859383CrossRefGoogle Scholar
  30. Fathy M, Nikaido T (2013) In vivo modulation of iNOS pathway in hepatocellular carcinoma by Nigella sativa. Environ Health Prev Med 18:377–385CrossRefGoogle Scholar
  31. Furnari FB, Huang HJ, Cavenee WK (1998) The phosphoinositol phosphatase activity of PTEN mediates a serum-sensitive G1 growth arrest in glioma cells. Cancer Res 58:5002–5008PubMedGoogle Scholar
  32. Gali-Muhtasib H, Diab-Assaf M, Boltze C et al (2004a) Thymoquinone extracted from black seed triggers apoptotic cell death in human colorectal cancer cells via a p53-dependent mechanism. Int J Oncol 25(4):857–866PubMedGoogle Scholar
  33. Gali-Muhtasib HU, Abou Kheir WG, Kheir LA et al (2004b) Molecular pathway for thymoquinone-induced cell-cycle arrest and apoptosis in neoplastic keratinocytes. Anti-Cancer Drugs 15(4):389–399CrossRefGoogle Scholar
  34. Gali-Muhtasib H, Kuester D, Mawrin C et al (2008) Thymoquinone triggers inactivation of the stress response pathway sensor CHEK1 and contributes to apoptosis in colorectal cancer cells. Cancer Res 68:5609–5618CrossRefGoogle Scholar
  35. Gurung RL, Lim SN, Khaw AK et al (2010) Thymoquinone induces telomere shortening, DNA damage and apoptosis in human glioblastoma cells. PLoS One 5(8):e12124CrossRefGoogle Scholar
  36. Harari PM, Allen GW, Bonner JA (2007) Biology of interactions: antiepidermal growth factor receptor agents. J Clin Oncol 25:4057–4065CrossRefGoogle Scholar
  37. Hosseinzadeh H, Parvardeh S, Asl MN et al (2007) Effect of thymoquinone and Nigella sativa seeds oil on lipid peroxidation level during global cerebral ischemia-reperfusion injury in rat hippocampus. Phytomedicine 14(9):621–627CrossRefGoogle Scholar
  38. Kabel AM, El-Rashidy MA, Omar MS (2016) Ameliorative potential of tamoxifen/thymoquinone combination in patients with breast cancer: a biochemical and immunohistochemical study. Cancer Med Anticancer Drug 1:102Google Scholar
  39. Kaseb AO, Chinnakannu K, Chen D et al (2007) Androgen receptor and E2F-1 targeted thymoquinone therapy for hormone-refractory prostate cancer. Cancer Res 67(16):7782–7788CrossRefGoogle Scholar
  40. Kensara OA, El-Shemi AG, Mohamed AM et al (2016) Thymoquinone subdues tumor growth and potentiates the chemopreventive effect of 5-fluorouracil on the early stages of colorectal carcinogenesis in rats. Drug Des Devel Ther 10:2239–2253CrossRefGoogle Scholar
  41. Kundu J, Choi BY, Jeong CH et al (2014) Thymoquinone induces apoptosis in human colon cancer HCT116 cells through inactivation of STAT3 by blocking JAK2- and Src mediated phosphorylation of EGF receptor tyrosine kinase. Oncol Rep 32(2):821–828CrossRefGoogle Scholar
  42. Lang M, Borgmann M, Oberhuber G et al (2013) Thymoquinone attenuates tumor growth in ApcMin mice by interference with Wnt-signaling. Mol Cancer 12(1):41CrossRefGoogle Scholar
  43. Laskar AA, Khan MA, Rahmani AH et al (2016) Thymoquinone, an active constituent of Nigella sativa seeds, binds with bilirubin and protects mice from hyperbilirubinemia and cyclophosphamide-induced hepatotoxicity. Biochimie 127:205–213CrossRefGoogle Scholar
  44. Lei X, Lv X, Liu M et al (2012) Thymoquinone inhibits growth and augments 5-fluorouracil-induced apoptosis in gastric cancer cells both in vitro and in vivo. Biochem Biophys Res Commun 417(2):864–868CrossRefGoogle Scholar
  45. Li F, Rajendran P, Sethi G (2010) Thymoquinone inhibits proliferation, induces apoptosis and chemosensitizes human multiple myeloma cells through suppression of signal transducer and activator of transcription 3 activation pathway. Br J Pharmacol 161:541–554CrossRefGoogle Scholar
  46. Motaghed M, Al-Hassan FM, Hamid SS (2013) Cellular responses with thymoquinone treatment in human breast cancer cell line MCF-7. Pharm Res 5(3):200–206Google Scholar
  47. Mu HQ, Yang S, Wang YJ et al (2012) Role of NF-κB in the anti-tumor effect of thymoquinone on bladder cancer. Zhonghua Yi Xue Za Zhi 92:392–396PubMedGoogle Scholar
  48. Ng WK, Yazan LS, Ismail M (2011) Thymoquinone from Nigella sativa was more potent than cisplatin in eliminating of SiHa cells via apoptosis with down-regulation of Bcl-2 protein. Toxicol In Vitro 25(7):1392–1398CrossRefGoogle Scholar
  49. Normanno N, De Luca A, Bianco C et al (2006) Epidermal growth factor receptor (EGFR) signaling in cancer. Gene 366:2–16CrossRefGoogle Scholar
  50. Odeh F, Odeh F, Ismail SI et al (2012) Thymoquinone in liposomes: a study of loading efficiency and biological activity towards breast cancer. Drug Deliv 19(8):371–377CrossRefGoogle Scholar
  51. Ohnishi Y, Lieger O, Attygalla M et al (2008) Effects of epidermal growth factor on the invasion activity of the oral cancer cell lines HSC3 and SAS. Oral Oncol 44:1155–1159CrossRefGoogle Scholar
  52. Paramasivam A, Sambantham S, Shabnam J et al (2012) Anti-cancer effects of thymoquinone in mouse neuroblastoma (Neuro-2a) cells through caspase-3 activation with down-regulation of XIAP. Toxicol Lett 213(2):151–159CrossRefGoogle Scholar
  53. Peng L, Liu A, Shen Y et al (2013) Antitumor and anti-angiogenesis effects of thymoquinone on osteosarcoma through the NF-κB pathway. Oncol Rep 29(2):571–578CrossRefGoogle Scholar
  54. Raghunandhakumar S, Paramasivam A, Senthilraja S et al (2013) Thymoquinone inhibits cell proliferation through regulation of G1/S phase cell cycle transition in N-nitrosodiethylamine-induced experimental rat hepatocellular carcinoma. Toxicol Lett 223(1):60–72CrossRefGoogle Scholar
  55. Rahmani AH, Aly SM (2015) Nigella sativa and its active constituent thymoquinone shows pivotal role in the diseases prevention and treatment. Asian J Pharm Clin Res 8:48–53Google Scholar
  56. Rahmani A, Alzohairy M, Khadri H et al (2012) Expressional evaluation of vascular endothelial growth factor (VEGF) protein in urinary bladder carcinoma patients exposed to cigarette smoke. Int J Clin Exp Pathol 5:195–202PubMedPubMedCentralGoogle Scholar
  57. Rahmani AH, Shabrmi FM, Aly SM (2014a) Active ingredients of ginger as potential candidates in the prevention and treatment of diseases via modulation of biological activities. Int J Physiol Pathophysiol Pharmacol 6:125–136PubMedPubMedCentralGoogle Scholar
  58. Rahmani AH, Al Zohairy MA, Aly SM et al (2014b) Curcumin: a potential candidate in prevention of cancer via modulation of molecular pathways. Biomed Res Int 2014:761608CrossRefGoogle Scholar
  59. Rahmani AH, Al Shabrmi FM, Allemailem KS et al (2015) Implications of green tea and its constituents in the prevention of cancer via the modulation of cell signalling pathway. Biomed Res Int 2015:2015Google Scholar
  60. Rajput S, Kumar BN, Dey KK et al (2013) Molecular targeting of Akt by thymoquinone promotes G (1) arrest through translation inhibition of cyclin D1 and induces apoptosis in breast cancer cells. Life Sci 93(21):783–790CrossRefGoogle Scholar
  61. Rajput S, Kumar BN, Banik P et al (2015) Thymoquinone restores radiation-induced TGF-β expression and abrogates EMT in chemoradiotherapy of breast cancer cells. J Cell Physiol 230(3):620–629CrossRefGoogle Scholar
  62. Sakalar C, Yuruk M, Kaya T et al (2013) Pronounced transcriptional regulation of apoptotic and TNF-NF-kappa-B signaling genes during the course of thymoquinone mediated apoptosis in HeLa cells. Mol Cell Biochem 383(1–2):243–251CrossRefGoogle Scholar
  63. Salim LZ, Mohan S, Othman R et al (2013) Thymoquinone induces mitochondria-mediated apoptosis in acute lymphoblastic leukaemia in vitro. Molecules 18(9):11219–11240CrossRefGoogle Scholar
  64. Salmena L, Carracedo A, Pandolfi PP et al (2008) Tenets of PTEN tumor suppression. Cell 133:403–414CrossRefGoogle Scholar
  65. Sayed-Ahmed MM, Aleisa AM, Al-Rejaie SS et al (2010) Thymoquinone attenuates diethylnitrosamine induction of hepatic carcinogenesis through antioxidant signaling. Oxidative Med Cell Longev 3:254–261CrossRefGoogle Scholar
  66. Sethi G, Ahn KS, Aggarwal BB (2008) Targeting nuclear factor-kappa B activation pathway by thymoquinone: role in suppression of antiapoptotic gene products and enhancement of apoptosis. Mol Cancer Res 6:1059–1070CrossRefGoogle Scholar
  67. Shoieb AM, Elgayyar M, Dudrick PS et al (2003) In vitro inhibition of growth and induction of apoptosis in cancer cell lines by thymoquinone. Int J Oncol 22(1):107–113PubMedGoogle Scholar
  68. Stewart BW, Wild CP (eds) (2014) Cancer etiology. World cancer report. World Health Organization. ISBN: 9283204298Google Scholar
  69. Taketo MM (1998) Cyclooxygenase-2 inhibitors in tumorigenesis (part II). J Natl Cancer Inst 90:1609–1620CrossRefGoogle Scholar
  70. Taylor WR, Stark GR (2001) Regulation of the G2/M transition by p53. Oncogene 20:1803–1815CrossRefGoogle Scholar
  71. Taysi S, Uslu C, Akcay F et al (2003) MDA and nitric oxide in the plasma of patients with advanced laryngeal cancer. Surg Today 33(9):651–654CrossRefGoogle Scholar
  72. Thomson LL, Lawton FG, Knowles RG et al (1994) NO synthase activity in human gynecological cancer. Cancer Res 54:1352–1354Google Scholar
  73. Torres MP, Ponnusamy MP, Chakraborty S et al (2010) Effects of thymoquinone in the expression of mucin 4 in pancreatic cancer cells: implications for the development of novel cancer therapies. Mol Cancer Ther 9(5):1419–1431CrossRefGoogle Scholar
  74. Ulasli SS, Celik S, Gunay E et al (2013) Anticancer effects of thymoquinone, caffeic acid phenethyl ester and resveratrol on A549 non-small cell lung cancer cells exposed to benzo(a)pyrene. Asian Pac J Cancer Prev 14(10):6159–6164CrossRefGoogle Scholar
  75. Umar S, Zargan J, Umar K et al (2012) Modulation of the oxidative stress and inflammatory cytokine response by thymoquinone in the collagen induced arthritis in Wistar rats. Chem Biol Interact 197(1):40–46CrossRefGoogle Scholar
  76. Waggoner SE (2003) Cervical cancer. Lancet 361(9376):2217–2225CrossRefGoogle Scholar
  77. Wang X, Jiang X (2008) PTEN: a default gate-keeping tumor suppressor with a versatile tail. Cell Res 18:807–816CrossRefGoogle Scholar
  78. Wilson AJ, Saskowski J, Barham W et al (2015) Microenvironmental effects limit efficacy of thymoquinone treatment in a mouse model of ovarian cancer. Mol Cancer 14:192CrossRefGoogle Scholar
  79. Wirries A, Breyer S, Quint K et al (2010) Thymoquinone hydrazone derivatives cause cell cycle arrest in p53-competent colorectal cancer cells. Exp Ther Med 1:369–375CrossRefGoogle Scholar
  80. Woo CC, Loo SY, Gee V et al (2011) Anticancer activity of thymoquinone in breast cancer cells: possible involvement of PPAR-γ pathway. Biochem Pharmacol 82(5):464–475CrossRefGoogle Scholar
  81. Woo CC, Kumar AP, Sethi G et al (2012) Thymoquinone: potential cure for inflammatory disorders and cancer. Biochem Pharmacol 83(4):443–451CrossRefGoogle Scholar
  82. Woo CC, Hsu A, Kumar AP et al (2013) Thymoquinone inhibits tumor growth and induces apoptosis in a breast cancer xenograft mouse model: the role of p38 MAPK and ROS. PLoS One 8(10):e75356CrossRefGoogle Scholar
  83. Wu ZH, Chen Z, Shen Y et al (2011) Anti-metastasis effect of thymoquinone on human pancreatic cancer. Yao Xue Xue Bao 46(8):910–914PubMedGoogle Scholar
  84. Yang J, Kuang XR, Lv PT et al (2015) Thymoquinone inhibits proliferation and invasion of human nonsmall-cell lung cancer cells via ERK pathway. Tumour Biol 36(1):259–269CrossRefGoogle Scholar
  85. Yi T, Cho SG, Yi Z et al (2008) Thymoquinone inhibits tumor angiogenesis and tumor growth through suppressing AKT and extracellular signal-regulated kinase signaling pathways. Mol Cancer Ther 7(7):1789–1796CrossRefGoogle Scholar
  86. Yu SM, Kim SJ (2013) Thymoquinone-induced reactive oxygen species causes apoptosis of chondrocytes via PI3K/Akt and p38kinase pathway. Exp Biol Med (Maywood) 238:811–820CrossRefGoogle Scholar
  87. Zhang L, Bai Y, Yang Y (2016) Thymoquinone chemosensitizes colon cancer cells through inhibition of NF-κB. Oncol Lett 12(4):2840–2845CrossRefGoogle Scholar
  88. Zhu W, Wang J, Guo X et al (2016) Thymoquinone inhibits proliferation in gastric cancer via the STAT3 pathway in vivo and in vitro. World J Gastroenterol 22(16):4149–4159CrossRefGoogle Scholar

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© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.College of Applied Medical SciencesQassim UniversityBuraidahSaudi Arabia

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