Lycopene sensitizes the cervical cancer cells to cisplatin via targeting nuclear factorkappa B (NF-κB) pathway

Lycopene sensitizes the cervical cancer cells to cisplatin via targeting nuclear factorkappa B (NF-κB) pathway

Background/aim: Lycopene is associated with anticancer effects in various tumor types. However, the exact underlying mechanisms of action of lycopene in human cervical cancer remain to be determined. This study aimed to determine anticancer efficacy and mechanism of lycopene in human cervical carcinoma (HeLa) cells. Materials and methods: HeLa cells were treated with cisplatin (1 µM) alone, lycopene (10 µM) alone, and in combination for 72 h. The cell viability of HeLa cells was assessed via MTS assay. Western blot was used to analyze the expression levels of the nuclear factor-kappa B (NF-κB), B-cell-associated X protein (Bax), nuclear factor erythroid 2-related factor (Nrf2), and B-cell lymphoma 2 (Bcl-2). Results: We found that lycopene acts as a synergistic agent with cisplatin in preventing the growth of HeLa cells. The rates of HeLa cells’ viability were 65.6% and 71.1% with lycopene and cisplatin treatment alone compared to the control group, respectively (P < 0.001). The inhibitory effect of cisplatin was enhanced with lycopene addition by declining the cell viability to 37.4% (P < 0.0001). Lycopene treatment significantly increased Bax expression (P < 0.0001) and decreased Bcl-2 expression (P < 0.0001) in HeLa cells. Furthermore, lycopene markedly activated the Nrf2 expression (P < 0.001) and suppressed the NF-κB signaling pathway (P < 0.0001). Conclusion: Lycopene increases the sensitization of cervical cancer cells to cisplatin via inhibition of cell viability, up-regulation of Bax expression, and down-regulation of Bcl-2 expression. Furthermore, the anticancer effect of lycopene might be also associated with suppression of NF-κB-mediated inflammatory responses, and modulation of Nrf2-mediated oxidative stress. The results of the present study suggest that lycopene and concurrent cisplatin chemotherapy might have a role in improving the treatment of cervical cancer.Key words: Lycopene, cervix cancer, cancer treatment, chemotherapy

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  • 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA: A Cancer Journal for Clinicians 2019; 69 (1): 7-34. doi: 10.3322/ caac.21551
  • 2. Thaxton L, Waxman AG. Cervical cancer prevention: immunization and screening 2015. Medical Clinics of North America 2015; 99 (3): 469-77. doi: 10.1016/j.mcna.2015.01.003
  • 3. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians 2018; 68 (6): 394-424. doi: 10.3322/caac.21492
  • 4. Tewari KS, Sill MW, Long III HJ, Penson RT, Huang H et al. Improved survival with bevacizumab in advanced cervical cancer. The New England Journal of Medicine 2014; 370 (8): 734-43. doi: 10.1056/NEJMoa1309748
  • 5. Zhu H, Luo H, Zhang W, Shen Z, Hu X et al. Molecular mechanisms of cisplatin resistance in cervical cancer. Drug Design, Development, and Therapy 2016; 10: 1885. doi: 10.2147/DDDT.S106412
  • 6. Nakanishi C, Toi M. Nuclear factor-κB inhibitors as sensitizers to anticancer drugs. Nature Reviews Cancer 2005; 5 (4): 297. doi: 10.1038/nrc1588
  • 7. Grivennikov SI, Karin M. Dangerous liaisons: STAT3 and NF-κB collaboration and crosstalk in cancer. Cytokine & Growth Factor Reviews 2010; 21 (1): 11-9. doi: 10.1016/j. cytogfr.2009.11.005
  • 8. Tilborghs S, Corthouts J, Verhoeven Y, Arias D, Rolfo C et al. The role of nuclear factor-kappa B signaling in human cervical cancer. Critical Reviews in Oncology/Hematology 2017; 120: 141-50. doi: 10.1016/j.critrevonc.2017.11.001
  • 9. Godwin P, Baird A-M, Heavey S, Barr M, O’Byrne K et al. Targeting nuclear factor-kappa B to overcome resistance to chemotherapy. Frontiers in Oncology 2013; 3 (16): 120. doi: 10.3389/fonc.2013.00120
  • 10. Wakabayashi N, Slocum SL, Skoko JJ, Shin S, Kensler TW. When NRF2 talks, who’s listening? Antioxidants & Redox Signaling 2010; 13 (11): 1649-63. doi: 10.1089/ars.2010.3216
  • 11. Lee J-M, Li J, Johnson DA, Stein TD, Kraft AD et al. Nrf2, a multi-organ protector? The FASEB Journal 2005; 19 (9): 1061- 6. doi: 10.1096/fj.04-2591hyp
  • 12. Ben-Neriah Y, Karin M. Inflammation meets cancer, with NFκB as the matchmaker. Nature Immunology 2011; 12 (8): 715. doi: 10.1038/ni.2060
  • 13. Chen J, Pu Z, Xiao Y, Li C, Du X et al. Lycopene synthesis via tri-cistronic expression of LeGGPS2, LePSY1 and crtI in Escherichia coli. Sheng Wu Gong Cheng Xue Bao = Chinese Journal of Biotechnology 2012; 28 (7): 823-33
  • 14. Zu K, Mucci L, Rosner BA, Clinton SK, Loda M et al. Dietary lycopene, angiogenesis, and prostate cancer: a prospective study in the prostate-specific antigen era. Journal of the National Cancer Institute 2014; 106 (2): djt430. doi: 10.1093/ jnci/djt430
  • 15. Bhuvaneswari V, Nagini S. Lycopene: a review of its potential as an anticancer agent. Current Medicinal Chemistry Anticancer Agents 2005; 5 (6): 627-35. doi: 10.2174/156801105774574667
  • 16. Teodoro AJ, Oliveira FL, Martins NB, de Azevedo Maia G, Martucci RB et al. Effect of lycopene on cell viability and cell cycle progression in human cancer cell lines. Cancer Cell International 2012; 12 (1): 36. doi: 10.1186/1475-2867-12-36
  • 17. Venkateswaran V, Venier NA, Colquhoun AJ, Fleshner NE, Klotz LH. Lycopene enhances the anti-proliferative and pro-apoptotic effects of capsaicin in prostate cancer in vitro. Journal of Cancer Therapeutics and Research 2012; 1 (1): 30. doi: 10.7243/2049-7962-1-30
  • 18. Jeong Y, Lim JW, Kim H. Lycopene inhibits reactive oxygen species-mediated NF-κB signaling and induces apoptosis in pancreatic cancer cells. Nutrients 2019; 11 (4): 762. doi: 10.3390/nu11040762
  • 19. Trejo-Solis C, Pedraza-Chaverri J, Torres-Ramos M, JimenezFarfan D, Cruz Salgado A et al. Multiple molecular and cellular mechanisms of action of lycopene in cancer inhibition. Evidence-Based Complementary and Alternative Medicine 2013; 2013: 705121. doi: 10.1155/2013/705121
  • 20. Assar EA, Vidalle MC, Chopra M, Hafizi S. Lycopene acts through inhibition of IκB kinase to suppress NF-κB signaling in human prostate and breast cancer cells. Tumor Biology 2016; 37 (7): 9375-85. doi: 10.1007/s13277-016-4798-3
  • 21. Johnstone RW, Ruefli AA, Lowe SW. Apoptosis: a link between cancer genetics and chemotherapy. Cell 2002; 108 (2): 153-64. doi: 10.1016/s0092-8674(02)00625-6
  • 22. Wang X. The expanding role of mitochondria in apoptosis. Genes & Development 2001; 15 (22): 2922-33.
  • 23. Adams JM, Cory S. The Bcl-2 protein family: arbiters of cell survival. Science (New York, NY) 1998; 281 (5381): 1322-6. doi: 10.1126/science.281.5381.1322
  • 24. Sahin K, Tuzcu M, Sahin N, Akdemir F, Ozercan I et al. Inhibitory effects of combination of lycopene and genistein on 7,12- dimethyl benz(a)anthracene-induced breast cancer in rats. Nutrition and Cancer 2011; 63 (8): 1279-86. doi: 10.1080/01635581.2011.606955
  • 25. Wang A, Zhang L. [Effect of lycopene on proliferation and cell cycle of hormone refractory prostate cancer PC-3 cell line]. Wei Sheng Yan Jiu = Journal of Hygiene and Research 2007; 36 (5): 575-8.
  • 26. Wang CY, Mayo MW, Korneluk RG, Goeddel DV, Baldwin AS, Jr. NF-kappaB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science (New York, NY) 1998; 281 (5383): 1680-3. doi: 10.1126/science.281.5383.1680
  • 27. Dai Y, Lawrence TS, Xu L. Overcoming cancer therapy resistance by targeting inhibitors of apoptosis proteins and nuclear factor-kappa B. American Journal of Translational Research 2009; 1 (1): 1-15.
  • 28. Palozza P, Colangelo M, Simone R, Catalano A, Boninsegna A et al. Lycopene induces cell growth inhibition by altering mevalonate pathway and Ras signaling in cancer cell lines. Carcinogenesis 2010; 31 (10): 1813-21. doi: 10.1093/carcin/ bgq157
  • 29. Li Y, Xing D, Chen Q, Chen WR. Enhancement of chemotherapeutic agent-induced apoptosis by inhibition of NF-kappaB using ursolic acid. International Journal of Cancer 2010; 127 (2): 462-73. doi: 10.1002/ijc.25044
  • 30. Huang CS, Fan YE, Lin CY, Hu ML. Lycopene inhibits matrix metalloproteinase-9 expression and down-regulates the binding activity of nuclear factor-kappa B and stimulatory protein-1. The Journal of Nutritional Biochemistry 2007; 18 (7): 449-56. doi: 10.1016/j.jnutbio.2006.08.007
  • 31. Moi P, Chan K, Asunis I, Cao A, Kan YW. Isolation of NFE2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region. Proceedings of the National Academy of Sciences of the United States of America 1994; 91 (21): 9926-30. doi: 10.1073/pnas.91.21.9926
  • 32. Kensler TW, Wakabayashi N. Nrf2: friend or foe for chemoprevention? Carcinogenesis 2010; 31 (1): 90-9. doi: 10.1093/carcin/bgp231
  • 33. Kensler TW, Wakabayashi N, Biswal S. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annual Review of Pharmacology and Toxicology 2007; 47: 89- 116. doi: 10.1146/annurev.pharmtox.46.120604.141046
  • 34. Thimmulappa RK, Mai KH, Srisuma S, Kensler TW, Yamamoto M et al. Identification of Nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray. Cancer Research 2002; 62 (18): 5196-203.
  • 35. Böttcher H, Eisbrenner K, Fritz S, Kindermann G, Kraxner F et al. An assessment of monitoring requirements and costs of ‘Reduced Emissions from Deforestation and Degradation’. Carbon Balance and Management 2009; 4 (1): 7. doi: 10.1186/1750-0680-4-7
  • 36. Ben-Dor A, Steiner M, Gheber L, Danilenko M, Dubi N et al. Carotenoids activate the antioxidant response element transcription system. Molecular Cancer Therapeutics 2005; 4 (1): 177-86.
  • 37. Bhuvaneswari V, Velmurugan B, Balasenthil S, Ramachandran CR, Nagini S. Chemopreventive efficacy of lycopene on 7,12-dimethylbenz[a]anthracene-induced hamster buccal pouch carcinogenesis. Fitoterapia 2001; 72 (8): 865-74. doi: 10.1016/s0367-326x(01)00321-5
  • 38. Lian F, Wang XD. Enzymatic metabolites of lycopene induce Nrf2-mediated expression of phase II detoxifying/antioxidant enzymes in human bronchial epithelial cells. International Journal of Cancer 2008; 123 (6): 1262-8. doi: 10.1002/ijc.23696
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