Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

KRAS Mutation Reduces Thymoquinone Anticancer Effects on Viability of Cells and Apoptosis

Author(s): Vildan Betul Yenigun*, Hasan Acar, Ebru Kanimdan, Alper Yenigun, Abdurrahim Kocyigit and Tulin Cora

Volume 23, Issue 15, 2023

Published on: 09 June, 2023

Page: [1747 - 1753] Pages: 7

DOI: 10.2174/1871520623666230517123807

Price: $65

Abstract

Background: Cancer is a life-threatening condition with an economic burden on societies. Phytotherapy is rapidly taking place in cancer research to increase the success of treatment and quality of life. Thymoquinone (TQ) is the main active phenolic compound obtained from the essential oil of the Nigella sativa (black cumin) plant seed. For a long time, black cumin has been used traditionally for the remedy of different diseases because of its various biological effects. It has been shown that most of these effects of black cumin seeds are due to TQ. TQ became a popular research topic for phytotherapy studies for its potential therapeutic applications, and more research is going on to fully understand its mechanisms of action, safety, and efficacy in humans. KRAS is a gene that regulates cell division and growth. Monoallelic variants in KRAS result in uncontrollable cell division, leading to cancer development. Studies have shown that cancer cells with KRAS mutations are often resistant to certain types of chemotherapy and targeted therapies.

Objective: This study aimed to compare the effect of TQ on cancer cells with and without KRAS mutation to better understand the reason why TQ may have different anticancer effects in the different types of cancer cells.

Methods: TQ was investigated for its cytotoxic and apoptotic effects in laryngeal cancer cells (HEp-2) without KRAS mutation and compared to mutant KRAS-transfected larynx cancer cells and KRAS mutation-carrying lung cancer cells (A549).

Results: We showed that TQ has more cytotoxic and apoptotic effects on laryngeal cancer cells without KRAS mutation than in cells with mutation.

Conclusion: KRAS mutations decrease the effect of TQ on cell viability and apoptosis, and further studies are needed to fully understand the relationship between KRAS mutations and thymoquinone effectiveness in cancer treatment.

Keywords: Cancer, KRAS mutation, phytotherapy, Nigella sativa, thymoquinone, chemotherapy.

Graphical Abstract
[1]
Das, D.N.; Panda, P.K.; Naik, P.P.; Mukhopadhyay, S.; Sinha, N.; Bhutia, S.K. Phytotherapeutic approach: A new hope for polycyclic aromatic hydrocarbons induced cellular disorders, autophagic and apoptotic cell death. Toxicol. Mech. Methods, 2017, 27(1), 1-17.
[http://dx.doi.org/10.1080/15376516.2016.1268228] [PMID: 27919191]
[2]
George, B.P.; Chandran, R.; Abrahamse, H. Role of phytochemicals in cancer chemoprevention: Insights. Antioxidants, 2021, 10(9), 1455.
[http://dx.doi.org/10.3390/antiox10091455] [PMID: 34573087]
[3]
Tan, B.L.; Norhaizan, M.E. Curcumin combination chemotherapy: The implication and efficacy in cancer. Molecules, 2019, 24(14), 2527.
[http://dx.doi.org/10.3390/molecules24142527] [PMID: 31295906]
[4]
Ali, B.H.; Blunden, G. Pharmacological and toxicological properties of Nigella sativa. Phytother. Res., 2003, 17(4), 299-305.
[http://dx.doi.org/10.1002/ptr.1309] [PMID: 12722128]
[5]
Badary, O.A.; Taha, R.A.; Gamal El-Din, A.M.; Abdel-Wahab, M.H. Thymoquinone is a potent superoxide anion scavenger. Drug Chem. Toxicol., 2003, 26(2), 87-98.
[http://dx.doi.org/10.1081/DCT-120020404] [PMID: 12816394]
[6]
Fatima Shad, K.; Soubra, W.; Cordato, D.J. The role of thymoquinone, a major constituent of Nigella sativa, in the treatment of inflammatory and infectious diseases. Clin. Exp. Pharmacol. Physiol., 2021, 48(11), 1445-1453.
[http://dx.doi.org/10.1111/1440-1681.13553] [PMID: 34297870]
[7]
Chaieb, K.; Kouidhi, B.; Jrah, H.; Mahdouani, K.; Bakhrouf, A. Antibacterial activity of thymoquinone, an active principle of Nigella sativa and its potency to prevent bacterial biofilm formation. BMC Complement. Altern. Med., 2011, 11(1), 29.
[http://dx.doi.org/10.1186/1472-6882-11-29] [PMID: 21489272]
[8]
Majdalawieh, A.F.; Yousef, S.M.; Abu-Yousef, I.A. Thymoquinone, a major constituent in Nigella sativa seeds, is a potential preventative and treatment option for atherosclerosis. Eur. J. Pharmacol., 2021, 909, 174420.
[http://dx.doi.org/10.1016/j.ejphar.2021.174420] [PMID: 34391767]
[9]
Saadat, S.; Aslani, M.R.; Ghorani, V.; Keyhanmanesh, R.; Boskabady, M.H. The effects ofNIGELLA SATIVA on respiratory, allergic and immunologic disorders, evidence from experimental and clinical studies, a comprehensive and updated review. Phytother. Res., 2021, 35(6), 2968-2996.
[http://dx.doi.org/10.1002/ptr.7003] [PMID: 33455047]
[10]
Mir, R.H.; Mir, P.A.; Mohi-ud-din, R.; Banday, N.; Maqbool, M.; Raza, S.N.; Farooq, S.; Afzal, S. Anticancer potential of thymoquinone: A novel bioactive natural compound from Nigella sativa L. Anticancer. Agents Med. Chem., 2022, 22(20), 3401-3415.
[http://dx.doi.org/10.2174/1871520622666220511233314] [PMID: 35546763]
[11]
Homayoonfal, M.; Asemi, Z.; Yousefi, B. Potential anticancer properties and mechanisms of thymoquinone in osteosarcoma and bone metastasis. Cell. Mol. Biol. Lett., 2022, 27(1), 21.
[http://dx.doi.org/10.1186/s11658-022-00320-0] [PMID: 35236304]
[12]
Ulasli, S.S.; Celik, S.; Gunay, E.; Ozdemir, M.; Hazman, O.; Ozyurek, A.; Koyuncu, T.; Unlu, M. 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., 2013, 14(10), 6159-6164.
[http://dx.doi.org/10.7314/APJCP.2013.14.10.6159] [PMID: 24289642]
[13]
Bashmail, H.A.; Alamoudi, A.A.; Noorwali, A.; Hegazy, G.A.; Ajabnoor, G.M.; Al-Abd, A.M. Thymoquinone enhances paclitaxel anti-breast cancer activity via inhibiting tumor-associated stem cells despite apparent mathematical antagonism. Molecules, 2020, 25(2), 426.
[http://dx.doi.org/10.3390/molecules25020426] [PMID: 31968657]
[14]
Zheng, M.; Mei, Z.; Junaid, M.; Tania, M.; Fu, J.; Chen, H.C.; Khan, M.A. Synergistic role of thymoquinone on anticancer activity of 5-fluorouracil in triple negative breast cancer cells. Anticancer. Agents Med. Chem., 2022, 22(6), 1111-1118.
[http://dx.doi.org/10.2174/1871520621666210624111613] [PMID: 34170813]
[15]
Adinew, G.M.; Messeha, S.S.; Taka, E.; Badisa, R.B.; Soliman, K.F.A. Anticancer effects of thymoquinone through the antioxidant activity, upregulation of Nrf2, and downregulation of PD-L1 in triple-negative breast cancer cells. Nutrients, 2022, 14(22), 4787.
[http://dx.doi.org/10.3390/nu14224787] [PMID: 36432484]
[16]
Woo, C.C.; Loo, S.Y.; Gee, V.; Yap, C.W.; Sethi, G.; Kumar, A.P.; Benny Tan, K.H. Anticancer activity of thymoquinone in breast cancer cells: Possible involvement of PPAR-γ pathway. Biochem. Pharmacol., 2011, 82(5), 464-475.
[http://dx.doi.org/10.1016/j.bcp.2011.05.030] [PMID: 21679698]
[17]
Junaid, M.; Akter, Y.; Afrose, S.S.; Tania, M.; Khan, M.A. Biological role of AKT and regulation of AKT signaling pathway by thymoquinone: Perspectives in cancer therapeutics. Mini Rev. Med. Chem., 2021, 21(3), 288-301.
[http://dx.doi.org/10.2174/18755607MTEweNDQp1] [PMID: 33019927]
[18]
Rooney, S.; Ryan, M.F. Effects of alpha-hederin and thymoquinone, constituents of Nigella sativa, on human cancer cell lines. Anticancer Res., 2005, 25(3B), 2199-2204.
[PMID: 16158964]
[19]
Alandağ, C.; Kancaği, D. D.; Karakuş Sir, G.; Çakirsoy, D.; Ovali, E.; Karaman, E.; Yüce, E.; Özdemir, F. The effects of thymoquinone on pancreatic cancer and immune cells. Rev. Assoc. Med. Bras., 2022, 68(8), 1023-1026.
[20]
Kranenburg, O. The KRAS oncogene: Past, present, and future. Biochim. Biophys. Acta, 2005, 1756(2), 81-82.
[PMID: 16269215]
[21]
Teo, M.Y.M.; Fong, J.Y.; Lim, W.M. Current advances and trends in KRAS targeted therapies for colorectal cancer. Mol. Cancer Res., 2021, 20(1), 30-44.
[22]
Lindsay, C.R.; Garassino, M.C.; Nadal, E.; Öhrling, K.; Scheffler, M.; Mazières, J. On target: Rational approaches to KRAS inhibition for treatment of non-small cell lung carcinoma. Lung Cancer, 2021, 160, 152-165.
[http://dx.doi.org/10.1016/j.lungcan.2021.07.005] [PMID: 34417059]
[23]
Langer, C.J. Exploring biomarkers in head and neck cancer. Cancer, 2012, 118(16), 3882-3892.
[http://dx.doi.org/10.1002/cncr.26718] [PMID: 22281752]
[24]
Bissada, E.; Abboud, O.; Abou, C.Z.; Guertin, L.; Weng, X.; Nguyen-Tan, P.F.; Tabet, J.C.; Thibaudeau, È.; Lambert, L.; Audet, M.L. Prevalence of K-RAS codons 12 and 13 mutations in locally advanced head and neck squamous cell carcinoma and impact on clinical outcomes. Int. J. Otolaryngol., 2013, 2013, 848021.
[http://dx.doi.org/10.1155/2013/848021]
[25]
Zhao, B.; Wang, L.; Qiu, H.; Zhang, M.; Sun, L.; Peng, P.; Yu, Q.; Yuan, X. Mechanisms of resistance to anti-EGFR therapy in colorectal cancer. Oncotarget, 2017, 8(3), 3980-4000.
[http://dx.doi.org/10.18632/oncotarget.14012] [PMID: 28002810]
[26]
Karapetis, C.S.; Khambata-Ford, S.; Jonker, D.J.; O’Callaghan, C.J.; Tu, D.; Tebbutt, N.C.; Simes, R.J.; Chalchal, H.; Shapiro, J.D.; Robitaille, S.; Price, T.J.; Shepherd, L.; Au, H.J.; Langer, C.; Moore, M.J.; Zalcberg, J.R. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N. Engl. J. Med., 2008, 359(17), 1757-1765.
[http://dx.doi.org/10.1056/NEJMoa0804385] [PMID: 18946061]
[27]
Wu, X.; Liu, P.C.; Liu, R.; Wu, X. Dual AO/EB staining to detect apoptosis in osteosarcoma cells compared with flow cytometry. Med. Sci. Monit. Basic Res., 2015, 21, 15-20.
[http://dx.doi.org/10.12659/MSMBR.893327] [PMID: 25664686]
[28]
Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2021, 71(3), 209-249.
[http://dx.doi.org/10.3322/caac.21660] [PMID: 33538338]
[29]
Buckner, C.A.; Lafrenie, R.M.; Dénommée, J.A.; Caswell, J.M.; Want, D.A. Complementary and alternative medicine use in patients before and after a cancer diagnosis. Curr. Oncol., 2018, 25(4), 275-281.
[http://dx.doi.org/10.3747/co.25.3884] [PMID: 30111972]
[30]
Efferth, T.; Saeed, M.E.M.; Mirghani, E.; Alim, A.; Yassin, Z.; Saeed, E.; Khalid, H.E.; Daak, S. Integration of phytochemicals and phytotherapy into cancer precision medicine. Oncotarget, 2017, 8(30), 50284-50304.
[http://dx.doi.org/10.18632/oncotarget.17466] [PMID: 28514737]
[31]
Cassileth, B.R.; Deng, G. Complementary and alternative therapies for cancer. Oncologist, 2004, 9(1), 80-89.
[http://dx.doi.org/10.1634/theoncologist.9-1-80] [PMID: 14755017]
[32]
Salem, M.L. Immunomodulatory and therapeutic properties of the Nigella sativa L. seed. Int. Immunopharmacol., 2005, 5(13-14), 1749-1770.
[http://dx.doi.org/10.1016/j.intimp.2005.06.008] [PMID: 16275613]
[33]
Dabeer, S.; Rather, M.A.; Rasool, S. History and traditional uses of black seeds (Nigella sativa). In: In Black Seeds (Nigella Sativa); Khan, A.; Rehman, M., Eds.; Elsevier, 2022; pp. 1-28.
[34]
Kus, G.; Ozkurt, M.; Kabadere, S.; Erkasap, N.; Goger, G.; Demirci, F. Antiproliferative and antiapoptotic effect of thymoquinone on cancer cells in vitro. Bratisl. Med. J., 2018, 119(5), 312-316.
[http://dx.doi.org/10.4149/BLL_2018_059] [PMID: 29749248]
[35]
Zhu, W.Q.; Wang, J.; Guo, X.F.; Liu, Z.; Dong, W.G. Thymoquinone inhibits proliferation in gastric cancer via the STAT3 pathway in vivo and in vitro. World J. Gastroenterol., 2016, 22(16), 4149-4159.
[http://dx.doi.org/10.3748/wjg.v22.i16.4149] [PMID: 27122665]
[36]
Attoub, S.; Sperandio, O.; Raza, H.; Arafat, K.; Al-Salam, S.; Al Sultan, M.A.; Al Safi, M.; Takahashi, T.; Adem, A. Thymoquinone as an anticancer agent: Evidence from inhibition of cancer cells viability and invasion in vitro and tumor growth in vivo. Fundam. Clin. Pharmacol., 2013, 27(5), 557-569.
[http://dx.doi.org/10.1111/j.1472-8206.2012.01056.x] [PMID: 22788741]
[37]
Wang, Y.; Yan, P.; Liu, Z.; Yang, X.; Wang, Y.; Shen, Z.; Bai, H.; Wang, J.; Wang, Z. MEK inhibitor can reverse the resistance to bevacizumab in A 549 cells harboring Kirsten rat sarcoma oncogene homolog mutation. Thorac. Cancer, 2016, 7(3), 279-287.
[http://dx.doi.org/10.1111/1759-7714.12325] [PMID: 27148412]
[38]
Burmi, R.S.; Maginn, E.N.; Gabra, H.; Stronach, E.A.; Wasan, H.S. Combined inhibition of the PI3K/mTOR/MEK pathway induces Bim/Mcl-1-regulated apoptosis in pancreatic cancer cells. Cancer Biol. Ther., 2019, 20(1), 21-30.
[http://dx.doi.org/10.1080/15384047.2018.1504718] [PMID: 30261145]
[39]
McCormick, F. KRAS as a therapeutic target. Clin. Cancer Res., 2015, 21(8), 1797-1801.
[http://dx.doi.org/10.1158/1078-0432.CCR-14-2662] [PMID: 25878360]
[40]
Timar, J.; Kashofer, K. Molecular epidemiology and diagnostics of KRAS mutations in human cancer. Cancer Metastasis Rev., 2020, 39(4), 1029-1038.
[http://dx.doi.org/10.1007/s10555-020-09915-5] [PMID: 32725342]
[41]
Huang, L.; Guo, Z.; Wang, F.; Fu, L. KRAS mutation: From undruggable to druggable in cancer. Signal Transduct. Target. Ther., 2021, 6(1), 386.
[http://dx.doi.org/10.1038/s41392-021-00780-4] [PMID: 34776511]
[42]
Knickelbein, K.; Zhang, L. Mutant KRAS as a critical determinant of the therapeutic response of colorectal cancer. Genes Dis., 2015, 2(1), 4-12.
[http://dx.doi.org/10.1016/j.gendis.2014.10.002] [PMID: 25815366]
[43]
Zhang, B.; Ting, W.J.; Gao, J.; Kang, Z.F.; Huang, C.Y.; Weng, Y.J. Erk phosphorylation reduces the thymoquinone toxicity in human hepatocarcinoma. Environ. Toxicol., 2021, 36(10), 1990-1998.
[http://dx.doi.org/10.1002/tox.23317] [PMID: 34173702]
[44]
Wu, C.S.; Wu, S.Y.; Chen, H.C.; Chu, C.A.; Tang, H.H.; Liu, H.S.; Hong, Y.R.; Huang, C.Y.F.; Huang, G.C.; Su, C.L. Curcumin functions as a MEK inhibitor to induce a synthetic lethal effect on KRAS mutant colorectal cancer cells receiving targeted drug regorafenib. J. Nutr. Biochem., 2019, 74, 108227.
[http://dx.doi.org/10.1016/j.jnutbio.2019.108227] [PMID: 31675556]
[45]
Althaiban, A.; Thyagarajan, A.; Prakash Sahu, R. KRAS pathway-based therapeutic approaches in pancreatic cancer. Mini Rev. Med. Chem., 2022, 12, 1870.
[PMID: 36573057]
[46]
Yi, T.; Cho, S.G.; Yi, Z.; Pang, X.; Rodriguez, M.; Wang, Y.; Sethi, G.; Aggarwal, B.B.; Liu, M. Thymoquinone inhibits tumor angiogenesis and tumor growth through suppressing AKT and extracellular signal-regulated kinase signaling pathways. Mol. Cancer Ther., 2008, 7(7), 1789-1796.
[http://dx.doi.org/10.1158/1535-7163.MCT-08-0124] [PMID: 18644991]
[47]
El-Baba, C.; Mahadevan, V.; Fahlbusch, F.B. S, S.M.; Rau, T.T.; Gali-Muhtasib, H.; Schneider-Stock, R. Thymoquinone-induced conformational changes of PAK1 interrupt prosurvival MEK-ERK signaling in colorectal cancer. Mol. Cancer, 2014, 13(1), 201.
[http://dx.doi.org/10.1186/1476-4598-13-201] [PMID: 25174975]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy