Novel antioxidants are not toxic to normal tissues but effectively kill cancer cells.
Journal: 2014/June - Cancer Biology and Therapy
ISSN: 1555-8576
Abstract:
Free radicals are formed as a result of cellular processes and play a key role in predisposition to and development of numerous diseases and of premature aging. Recently, we reported the syntheses of a number of novel phenolic antioxidants for possible application in food industry. In the present study, analyses of the cellular processes and molecular gene expression effects of some of the novel antioxidants in normal human tissues and in cancer cells were undertaken. Results indicated that whereas the examined antioxidants showed no effects on morphology and gene expression of normal human oral and gingival epithelial tissues, they exerted a profound cell killing effect on breast cancer cells, including on chemotherapy-resistant breast cancer cells and on oral squamous carcinoma cells. Among the tested antioxidants, N-decyl-N-(3-methoxy-4-hydroxybenzyl)-3-(3,4-dihydroxyphenyl) propanamide and N-decyl-N-(3,5-dimethoxy-4-hydroxybenzyl)-3-(3,4-dihydroxyphenyl) propanamide were the most promising, with excellent potential for cancer treatment. Moreover, our gene expression databases can be used as a roadmap for future analysis of mechanisms of antioxidant action.
Relations:
Content
Citations
(1)
References
(38)
Chemicals
(10)
Organisms
(1)
Processes
(2)
Anatomy
(1)
Affiliates
(1)
Similar articles
Articles by the same authors
Discussion board
Cancer Biol Ther 14(10): 907-915

Novel antioxidants are not toxic to normal tissues but effectively kill cancer cells

Additional material

Click here to view.(255K, pdf)
Department of Chemistry; University of Lethbridge; Lethbridge, AB Canada
Department of Biological Sciences; University of Lethbridge; Lethbridge, AB Canada
Correspondence to: Olga Kovalchuk, Email: ac.htelu@kuhclavok.aglo
Received 2012 Dec 20; Revised 2013 Jul 18; Accepted 2013 Jul 29.

Abstract

Free radicals are formed as a result of cellular processes and play a key role in predisposition to and development of numerous diseases and of premature aging. Recently, we reported the syntheses of a number of novel phenolic antioxidants for possible application in food industry. In the present study, analyses of the cellular processes and molecular gene expression effects of some of the novel antioxidants in normal human tissues and in cancer cells were undertaken. Results indicated that whereas the examined antioxidants showed no effects on morphology and gene expression of normal human oral and gingival epithelial tissues, they exerted a profound cell killing effect on breast cancer cells, including on chemotherapy-resistant breast cancer cells and on oral squamous carcinoma cells. Among the tested antioxidants, N-decyl-N-(3-methoxy-4-hydroxybenzyl)-3-(3,4-dihydroxyphenyl) propanamide and N-decyl-N-(3,5-dimethoxy-4-hydroxybenzyl)-3-(3,4-dihydroxyphenyl) propanamide were the most promising, with excellent potential for cancer treatment. Moreover, our gene expression databases can be used as a roadmap for future analysis of mechanisms of antioxidant action.

Keywords: free radicals, antioxidants, gene expression, human 3D tissues, breast cancer, oral cancer
Abstract

Acknowledgments

We are grateful to Jody Filkowski for running the Illumina array expression, to Dr Vasyl Chekhun for the gift of MCF-7/DOX and MCF-7/cisDDP cells, and to Dr Joseph Dort for the gift of OSCC cell lines. Research in the Kovalchuk laboratory was supported by the Alberta Cancer Foundation, CIHR, and NSERC. Research in the Przybylski laboratory was supported by the Alberta Funding Consortium and the Alberta Value Added Corporation.

Acknowledgments

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Disclosure of Potential Conflicts of Interest

Footnotes

Previously published online: www.landesbioscience.com/journals/cbt/article/25935

Footnotes

References

  • 1. Rosanna DP, Salvatore CReactive oxygen species, inflammation, and lung diseases. Curr Pharm Des. 2012;18:3889–900. doi: 10.2174/138161212802083716.] [[PubMed][Google Scholar]
  • 2. Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser JFree radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol. 2007;39:44–84. doi: 10.1016/j.biocel.2006.07.001.] [[PubMed][Google Scholar]
  • 3. Dröge WFree radicals in the physiological control of cell function. Physiol Rev. 2002;82:47–95.[PubMed][Google Scholar]
  • 4. Ray PD, Huang BW, Tsuji YReactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell Signal. 2012;24:981–90. doi: 10.1016/j.cellsig.2012.01.008.] [[Google Scholar]
  • 5. Florence TMThe role of free radicals in disease. Aust N Z J Ophthalmol. 1995;23:3–7. doi: 10.1111/j.1442-9071.1995.tb01638.x.] [[PubMed][Google Scholar]
  • 6. Moreira PI, Santos MS, Oliveira CR, Shenk JC, Nunomura A, Smith MA, Zhu X, Perry GAlzheimer disease and the role of free radicals in the pathogenesis of the disease. CNS Neurol Disord Drug Targets. 2008;7:3–10. doi: 10.2174/187152708783885156.] [[PubMed][Google Scholar]
  • 7. Catel Y, Aladedunye F, Przybylski RSynthesis, Radical Scavenging Activity, Protection during Storage, and Frying by Novel Antioxidants. J Agric Food Chem. 2010 doi: 10.1021/jf102287h.] [[PubMed][Google Scholar]
  • 8. Flora SJRole of free radicals and antioxidants in health and disease. Cell Mol Biol (Noisy-le-grand) 2007;53:1–2.[PubMed][Google Scholar]
  • 9. German JBFood processing and lipid oxidation. Adv Exp Med Biol. 1999;459:23–50. doi: 10.1007/978-1-4615-4853-9_3.] [[PubMed][Google Scholar]
  • 10. Aladedunye F, Catel Y, Przybylski RNovel caffeic acid amide antioxidants: Synthesis, radical scavenging activity and performance under storage and frying conditions. Food Chem. 2012;130:945–52. doi: 10.1016/j.foodchem.2011.08.021.[PubMed][Google Scholar]
  • 11. Gordon MHSignificance of dietary antioxidants for health. Int J Mol Sci. 2012;13:173–9. doi: 10.3390/ijms13010173.] [[Google Scholar]
  • 12. Catel Y, Aladedunye F, Przybylski RSynthesis, Radical Scavenging Activity, Protection during Storage, and Frying by Novel Antioxidants. J Agric Food Chem. 2010;58:11081–9. doi: 10.1021/jf102287h.] [[PubMed][Google Scholar]
  • 13. Catel Y, Aladedunye F, Przybylski RRadical Scavenging Activity and Performance of Novel Phenolic Antioxidants in Oils During Storage and Frying. J Am Oil Chem Soc. 2012;89:55–66. doi: 10.1007/s11746-011-1889-6.[PubMed][Google Scholar]
  • 14. Wu MH, Tsai YT, Hua KT, Chang KC, Kuo ML, Lin MTEicosapentaenoic acid and docosahexaenoic acid inhibit macrophage-induced gastric cancer cell migration by attenuating the expression of matrix metalloproteinase 10. J Nutr Biochem. 2012;23:1434–9. doi: 10.1016/j.jnutbio.2011.09.004.] [[PubMed][Google Scholar]
  • 15. Proctor GB, Carpenter GHRegulation of salivary gland function by autonomic nerves. Auton Neurosci. 2007;133:3–18. doi: 10.1016/j.autneu.2006.10.006.] [[PubMed][Google Scholar]
  • 16. Steenhuis P, Huntley RE, Gurenko Z, Yin L, Dale BA, Fazel N, Isseroff RRAdrenergic signaling in human oral keratinocytes and wound repair. J Dent Res. 2011;90:186–92. doi: 10.1177/0022034510388034.] [[Google Scholar]
  • 17. Baron V, Adamson ED, Calogero A, Ragona G, Mercola DThe transcription factor Egr1 is a direct regulator of multiple tumor suppressors including TGFbeta1, PTEN, p53, and fibronectin. Cancer Gene Ther. 2006;13:115–24. doi: 10.1038/sj.cgt.7700896.] [[Google Scholar]
  • 18. Ellisen LWGrowth control under stress: mTOR regulation through the REDD1-TSC pathway. Cell Cycle. 2005;4:1500–2. doi: 10.4161/cc.4.11.2139.] [[PubMed][Google Scholar]
  • 19. Stivala LA, Cazzalini O, Prosperi EThe cyclin-dependent kinase inhibitor p21CDKN1A as a target of anti-cancer drugs. Curr Cancer Drug Targets. 2012;12:85–96. doi: 10.2174/156800912799095126.] [[PubMed][Google Scholar]
  • 20. Langerak P, Russell PRegulatory networks integrating cell cycle control with DNA damage checkpoints and double-strand break repair. Philos Trans R Soc Lond B Biol Sci. 2011;366:3562–71. doi: 10.1098/rstb.2011.0070.] [[Google Scholar]
  • 21. Mavers M, Balomenos D, Perlman HThe cyclin dependent kinase inhibitor p21((WAF1/C1P1)) Arthritis Rheum. 2008;58:S933–933.[PubMed][Google Scholar]
  • 22. Rogakou EP, Pilch DR, Orr AH, Ivanova VS, Bonner WMDNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J Biol Chem. 1998;273:5858–68. doi: 10.1074/jbc.273.10.5858.] [[PubMed][Google Scholar]
  • 23. Ivashkevich A, Redon CE, Nakamura AJ, Martin RF, Martin OAUse of the γ-H2AX assay to monitor DNA damage and repair in translational cancer research. Cancer Lett. 2012;327:123–33. doi: 10.1016/j.canlet.2011.12.025.] [[Google Scholar]
  • 24. Dickey JS, Redon CE, Nakamura AJ, Baird BJ, Sedelnikova OA, Bonner WMH2AX: functional roles and potential applications. Chromosoma. 2009;118:683–92. doi: 10.1007/s00412-009-0234-4.] [[Google Scholar]
  • 25. Williams RS, Williams JS, Tainer JAMre11-Rad50-Nbs1 is a keystone complex connecting DNA repair machinery, double-strand break signaling, and the chromatin template. Biochem Cell Biol. 2007;85:509–20. doi: 10.1139/O07-069.] [[PubMed][Google Scholar]
  • 26. Cazzalini O, Scovassi AI, Savio M, Stivala LA, Prosperi EMultiple roles of the cell cycle inhibitor p21(CDKN1A) in the DNA damage response. Mutat Res. 2010;704:12–20. doi: 10.1016/j.mrrev.2010.01.009.] [[PubMed][Google Scholar]
  • 27. Sedelnikova OA, Pilch DR, Redon C, Bonner WMHistone H2AX in DNA damage and repair. Cancer Biol Ther. 2003;2:233–5. doi: 10.4161/cbt.2.3.373.] [[PubMed][Google Scholar]
  • 28. Iorio MV, Croce CMmicroRNA involvement in human cancer. Carcinogenesis. 2012;33:1126–33. doi: 10.1093/carcin/bgs140.] [[Google Scholar]
  • 29. Fesik SWPromoting apoptosis as a strategy for cancer drug discovery. Nat Rev Cancer. 2005;5:876–85. doi: 10.1038/nrc1736.] [[PubMed][Google Scholar]
  • 30. Lin CJ, Grandis JR, Carey TE, Gollin SM, Whiteside TL, Koch WM, Ferris RL, Lai SYHead and neck squamous cell carcinoma cell lines: established models and rationale for selection. Head Neck. 2007;29:163–88. doi: 10.1002/hed.20478.] [[PubMed][Google Scholar]
  • 31. Chekhun VF, Lukyanova NY, Kovalchuk O, Tryndyak VP, Pogribny IPEpigenetic profiling of multidrug-resistant human MCF-7 breast adenocarcinoma cells reveals novel hyper- and hypomethylated targets. Mol Cancer Ther. 2007;6:1089–98. doi: 10.1158/1535-7163.MCT-06-0663.] [[PubMed][Google Scholar]
  • 32. Ramqvist T, Dalianis TAn epidemic of oropharyngeal squamous cell carcinoma (OSCC) due to human papillomavirus (HPV) infection and aspects of treatment and prevention. Anticancer Res. 2011;31:1515–9.[PubMed][Google Scholar]
  • 33. Poh CF, Durham JS, Brasher PM, Anderson DW, Berean KW, MacAulay CE, Lee JJ, Rosin MPCanadian Optically-guided approach for Oral Lesions Surgical (COOLS) trial: study protocol for a randomized controlled trial. BMC Cancer. 2011;11:462. doi: 10.1186/1471-2407-11-462.] [[Google Scholar]
  • 34. Mitchell D, Paniker L, Godar DNucleotide excision repair is reduced in oral epithelial tissues compared with skin. Photochem Photobiol. 2012;88:1027–32. doi: 10.1111/j.1751-1097.2012.01163.x.] [[Google Scholar]
  • 35. Koschier F, Kostrubsky V, Toole C, Gallo MAIn vitro effects of ethanol and mouthrinse on permeability in an oral buccal mucosal tissue construct. Food Chem Toxicol. 2011;49:2524–9. doi: 10.1016/j.fct.2011.06.018.] [[PubMed][Google Scholar]
  • 36. Harris T, Jimenez L, Kawachi N, Fan JB, Chen J, Belbin T, Ramnauth A, Loudig O, Keller CE, Smith R, et al Low-level expression of miR-375 correlates with poor outcome and metastasis while altering the invasive properties of head and neck squamous cell carcinomas. Am J Pathol. 2012;180:917–28. doi: 10.1016/j.ajpath.2011.12.004.] [[Google Scholar]
  • 37. Wang J, Huang H, Wang C, Liu X, Hu F, Liu MMicroRNA-375 sensitizes tumour necrosis factor-alpha (TNF-α)-induced apoptosis in head and neck squamous cell carcinoma in vitro. Int J Oral Maxillofac Surg. 2013;42:949–55. doi: 10.1016/j.ijom.2013.04.016.] [[PubMed][Google Scholar]
  • 38. Ding LH, Xie Y, Park S, Xiao G, Story MDEnhanced identification and biological validation of differential gene expression via Illumina whole-genome expression arrays through the use of the model-based background correction methodology. Nucleic Acids Res. 2008;36:e58. doi: 10.1093/nar/gkn234.] [[Google Scholar]
  • 39. Kovalchuk O, Zemp FJ, Filkowski JN, Altamirano AM, Dickey JS, Jenkins-Baker G, Marino SA, Brenner DJ, Bonner WM, Sedelnikova OAmicroRNAome changes in bystander three-dimensional human tissue models suggest priming of apoptotic pathways. Carcinogenesis. 2010;31:1882–8. doi: 10.1093/carcin/bgq119.] [[Google Scholar]
  • 40. Simpson RJRapid coomassie blue staining of protein gels. Cold Spring Harb Protoc. 2010;2010:t5413. doi: 10.1101/pdb.prot5413.] [[PubMed][Google Scholar]
  • 41. Koopman G, Reutelingsperger CP, Kuijten GA, Keehnen RM, Pals ST, van Oers MHAnnexin V for flow cytometric detection of phosphatidylserine expression on B cells undergoing apoptosis. Blood. 1994;84:1415–20.[PubMed][Google Scholar]
  • 42. Huang W, Sherman BT, Lempicki RASystematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009;4:44–57. doi: 10.1038/nprot.2008.211.] [[PubMed][Google Scholar]
Collaboration tool especially designed for Life Science professionals.Drag-and-drop any entity to your messages.