Cinnamaldehyde and eugenol change the expression folds of AKT1 and DKC1 genes and decrease the telomere length of human adipose-derived stem cells (hASCs): An experimental and in silico study

Document Type: Original Article


1 Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

2 Department of Anatomical Sciences, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

3 Shefa Neuroscience Research Center, Khatam Alanbia Hospital, Tehran, Iran


Objective(s): To investigate the effect of cinnamaldehyde and eugenol on the telomere-dependent senescence of stem cells. In addition, to search the probable targets of mentioned phytochemicals between human telomere interacting proteins (TIPs) using in silico studies.
Materials and Methods: Human adipose derived stem cells (hASCs) were studied under treatments with 2.5 µM/ml cinnamaldehyde, 0.1 µg/ml eugenol, 0.01% DMSO or any additive. The expression of TERT, AKT1 and DKC1 genes and the telomere length were assessed over 48-hr treatment. In addition, docking study was conducted to show probable ways through which phytochemicals interact with TIPs.
Results: Treated and untreated hASCs had undetectable TERT expression, but they did affect the AKT1 and DKC1 expression levels (CI=0.95; P<0.05). The telomere lengths reduced in phytochemicals treated with hASCs when compared with the untreated cells (P<0.05). Docking results showed that the TIPs might be the proper targets for cinnamaldehyde and eugenol. Data mining showed there are many targets for cinnamaldehyde and eugenol in the intracellular environment.
Conclusion: The general effect of cinnamaldehyde and eugenol is their induction of stem cell senescence. Therefore, they could be applicable as chemo-preventive or antineoplastic agents.


1. Flores I, Blasco MA. The role of telomeres and telomerase in stem cell aging. FEBS Lett 2010; 584:3826-3830.

2. Wong C-C, Li H-B, Cheng K-W, Chen F. A systematic survey of antioxidant activity of 30 Chinese medicinal plants using the ferric reducing antioxidant power assay. Food Chem 2006; 97:705-711.

3. Zaveri NT. Green tea and its polyphenolic catechins: Medicinal uses in cancer and noncancer applications. Life Sci 2006; 78:2073-2080.

4. Ho YS, So KF, Chang RCC. Anti-aging herbal medicine—How and why can they be used in aging-associated neurodegenerative diseases? Ageing Res Rev 2010; 9:354-362.

5. Ogata M, Hoshi M, Urano S, Endo T. Antioxidant activity of eugenol and related monomeric and dimeric compounds. Chem Pharm Bull 2000; 48:1467-1469.

6. Fang SH, Rao YK, Tzeng YM. Cytotoxic effect of trans-cinnamaldehyde from cinnamomum osmo-phloeum leaves on Human cancer cell lines. Int J Appl Sci Eng 2004; 2:136-147.

7. Jaganathan SK, Mazumdar A, Mondhe D, Mandal M. Apoptotic effect of eugenol in human colon cancer cell lines. Cell Biol Int 2011; 35:607-15.

8. Chuang LY, Guh JY, Chao LK, Lu YC, Hwang JY, Yang YL, et al. Anti-proliferative effects of cinnamaldehyde on human hepatoma cell lines. Food Chem 2012; 133:1603-1610.

9. King AA, Shaughnessy DT, Mure K, Leszczynska J, Ward WO, Umbach DM, et al. Antimutagenicity of cinnamaldehyde and vanillin in human cells: Global gene expression and possible role of DNA damage and repair. Mutat Res 2007; 616:60-69.

10. Chao LK, Hua KF, Hsu HY, Cheng SS, Lin IF, Chen CJ, et al. Cinnamaldehyde inhibits pro-inflammatory cytokines secretion from monocytes/macrophages through suppression of intracellular signaling. Food Chem Toxicol 2008; 46:220-231.

11. Tao G, Irie Y, Li D-J, Keung WM. Eugenol and its structural analogs inhibit monoamine oxidase A and exhibit antidepressant-like activity. Bioorgan Med Chem 2005; 13:4777-47788.

12. Absalan A, Mesbah-Namin SA, Tiraihi T, Taheri T. The effects of cinnamaldehyde and eugenol on human adipose-derived mesenchymal stem cells viability, growth and differentiation: a cheminformatics and in vitro study. Avicenna J Phytomed 2016; 1-11.

13. Dokal I. Dyskeratosis congenita. Hematology Am Soc Hematol Educ Program 201; 1:480-486.

14. Plunkett FJ, Franzese O, Finney HM, Fletcher JM, Belaramani LL, Salmon M, et al. The loss of telomerase activity in highly differentiated CD8+CD28-CD27- T cells is associated with decreased Akt (Ser473) phosphorylation. J Immunol 2007; 178:7710-7719.

15. Kuzuhara T, Suganuma M, Fujiki H. Green tea catechin as a chemical chaperone in cancer prevention. Cancer Lett 2008; 261:12-20.

16. Aggarwal S, Ichikawa H, Takada Y, Sandur SK, Shishodia S, Aggarwal BB. Curcumin (diferuloylmethane) down-regulates expression of cell proliferation and antiapoptotic and metastatic gene products through suppression of IκBα kinase and Akt activation. Mol Pharmacol 2006; 69:195-206.

17. O’Callaghan NJ, Fenech M. A quantitative PCR method for measuring absolute telomere length. Biol Proced Online 2011; 13:1-10.

18. Podlevsky JD, Bley CJ, Omana RV, Qi X, Chen JJ. The telomerase database. Nucleic Acids Res 2008; 36:D339-D343.

19. Kiefer F, Arnold K, Künzli M, Bordoli L, Schwede T. The SWISS-MODEL Repository and associated resources. Nucleic Acids Res 2009; 37: D387-D92.

20. Arnold K, Bordoli L, Kopp J, Schwede T. The SWISS-MODEL Workspace: A web-based environment for protein structure homology modelling. Bioinformatics 2006; 22:195-201.

21. Irwin JJ, Shoichet BK. ZINC-a free database of commercially available compounds for virtual screening. J Chem Inf Model 2005; 45:177-182.

22. Thomsen R, Christensen MH. MolDock: a new technique for high-accuracy molecular docking. J Med Chem 2006; 49:3315-3321.

23. Franceschini A, Szklarczyk D, Frankild S, Kuhn M, Simonovic M, Roth A, et al. STRING v9.1: protein-protein interaction networks, with increased coverage and integration. Nucleic Acids Res 2013; 41:D808-815.

24. Zimmermann S, Voss M, Kaiser S, Kapp U, Waller CF, Martens UM. Lack of telomerase activity in human mesenchymal stem cells. Leukemia 2003; 17:1146-1149.

25. Python F, Goebel C, Aeby P. Comparative DNA microarray analysis of human monocyte derived dendritic cells and MUTZ-3 cells exposed to the moderate skin sensitizer cinnamaldehyde. Toxicol Appl Pharmacol 2009; 239:273-283.

26. Aviv A, Hunt SC, Lin J, Cao X, Kimura M, Blackburn E. Impartial comparative analysis of measurement of leukocyte telomere length/DNA content by Southern blots and qPCR. Nucleic Acids Res 2011; 39:e134.

27. Murakami A, Ohnishi K. Mechanisms underlying food functionality via molecular chaperones: chemical training hypothesis. J Food Drug Anal 2012; 20:257-260.

28. Grover A, Shandilya A, Agrawal V, Pratik P, Bhasme D, Bisaria VS, et al. Hsp90/Cdc37 Chaperone/co-chaperone complex, a novel junction anticancer target elucidated by the mode of action of herbal drug Withaferin A. BMC Bioinformatics 2011; 12:S30.

29. Gruber JV, Holtz R. Examining the genomic influence of skin antioxidants in vitro. Mediat Inflamm 2010; 2010. pii: 230450.

30. Shervington A, Pawar V, Menon S, Thakkar D, Patel R. The sensitization of glioma cells to cisplatin and tamoxifen by the use of catechin. Mol Biol Rep 2009; 36:1181-1186.

31. Magkoufopoulou C, Claessen S, Jennen D, Kleinjans J, van Delft J. Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis 2011; 26:593-604.

32. Strati A, Papoutsi Z, Lianidou E, Moutsatsou P. Effect of ellagic acid on the expression of human telomerase reverse transcriptase (hTERT) α+ β+ transcript in estrogen receptor-positive MCF-7 breast cancer cells. Clin Biochem 2009; 42:1358-1362.

33. Paradise A, Levin MK, Korza G, Carson JH. Significant proportions of nuclear transport proteins with reduced intracellular mobilities resolved by fluorescence correlation spectroscopy. J Mol Biol 2007; 365:50-65.

34. Blackburn EH. Switching and signaling at the telomere. Cell 2001; 106:661-673.

35. LaBranche H, Dupuis S, Ben-David Y, Bani MR, Wellinger RJ, Chabot B. Telomere elongation by hnRNP A1 and a derivative that interacts with telomeric repeats and telomerase. Nat Genet 1998; 19:199-202.

36. Fiset S, Chabot B. hnRNP A1 may interact simultaneously with telomeric DNA and the human telomerase RNA in vitro. Nucleic Acids Res 2001; 29:2268-2275.

37. Thompson DC, Constantin-Teodosiu D, Moldéus P. Metabolism and cytotoxicity of eugenol in isolated rat hepatocytes. Chem Biol Interact 1991; 77:137-147.

38. Weibel H, Hansen J. Interaction of cinnamaldehyde (a sensitizer in fragrance) with protein. Contact Dermatitis 1989; 20:161-166.

39. Bahar I, Chennubhotla C, Tobi D. Intrinsic dynamics of enzymes in the unbound state and relation to allosteric regulation. Curr Opin Struct Biol 2007; 17:633-640.

40. Mount DW, Pandey R. Using bioinformatics and genome analysis for new therapeutic interventions. Mol Cancer Ther 2005; 4:1636-1643.

41. Zhang JH, Liu LQ, He YL, Kong WJ, Huang SA. Cytotoxic effect of trans-cinnamaldehyde on human leukemia K562 cells. Acta Pharmacol Sin 2010; 31:861-866.