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


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Аннотация

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.

Об авторах

Vildan Betul Yenigun

Department of Medical Biochemistry, Faculty of Medicine, Bezmialem Vakif University

Автор, ответственный за переписку.
Email: info@benthamscience.net

Hasan Acar

Department of Medical Genetics, University of Health Sciences

Email: info@benthamscience.net

Ebru Kanimdan

Department of Medical Biochemistry, Faculty of Medicine, Bezmiâlem Vakıf Üniversitesi

Email: info@benthamscience.net

Alper Yenigun

Department of Otorhinolaryngology, Faculty of Medicine, Bezmialem Vakif University

Email: info@benthamscience.net

Abdurrahim Kocyigit

Department of Medical Biochemistry, Faculty of Medicine, Bezmialem Vakif University

Email: info@benthamscience.net

Tulin Cora

Department of Medical Genetics, Faculty of Medicine, Selçuk University

Email: info@benthamscience.net

Список литературы

  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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 10.18632/oncotarget.17466 PMID: 28514737
  31. Cassileth, B.R.; Deng, G. Complementary and alternative therapies for cancer. Oncologist, 2004, 9(1), 80-89. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 10.1080/15384047.2018.1504718 PMID: 30261145
  39. McCormick, F. KRAS as a therapeutic target. Clin. Cancer Res., 2015, 21(8), 1797-1801. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 10.1186/1476-4598-13-201 PMID: 25174975

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