Abstract
Current plant-derived anticancer therapeutics aim to reach higher effectiveness, to potentiate chemosensitivity and minimize the toxic side effects compared to conventional chemotherapy. Cotinus coggygria Scop. is a herb with high pharmacological potential, widely applied in traditional phytotherapy. Our previous study revealed that leaf aqueous ethanolic extract from C. coggygria exerts in vitro anticancer activity on human breast, ovarian and cervical cancer cell lines. The objective of the present research was to investigate possible molecular mechanisms and targets of the antitumor activity of the extract in breast cancer MCF7 cells through analysis of cell cycle and apoptosis, clonogenic ability assessment, evaluation of the extract genotoxic capacity, characterization of cells thermodynamic properties, and analysis on the expression of genes involved in cellular epigenetic processes. The obtained results indicated that in MCF7 cells C. coggygria extract causes S phase cell cycle arrest and triggers apoptosis, reduces colony formation, induces DNA damage, affects cellular thermodynamic parameters, and tends to inhibit the relative expression of DNMT1, DNMT3a, MBD3, and p300. Further studies on the targeted molecules and the extract anti-breast cancer potential on animal experimental model system, need to be performed in the future.
Funding source: European Social Fund, Operational Programme Human Resources Development and Bulgarian Ministry of Education and Science
Award Identifier / Grant number: BG051PO001-3.3.06-0025
Funding source: Bulgarian Academy of Sciences
Award Identifier / Grant number: DFNP-208/16.05.2016
Acknowledgments
The authors are grateful to Vemo 99 Ltd. for providing the extract of Cotinus coggygria. Cell line used in the analysis was supplied by project DO-02-310/08.
Author contribution: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: This work was partially supported by the grant №BG051PO001-3.3.06-0025, financed by the European Social Fund and Operational Programme Human Resources Development (2007–2013) and co-financed by Bulgarian Ministry of Education and Science and by the Program for support of young scientists, Bulgarian Academy of Sciences, contract DFNP-208/16.05.2016.
Conflict of interest statement: The authors declare no conflicts of interest regarding this article.
References
1. Bray, F, Ferlay, J, Soerjomataram, I, Siegel, RL, Torre, LA, Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394–424. https://doi.org/10.3322/caac.21492.Search in Google Scholar
2. Newman, DJ, Cragg, GM. Natural products as sources of new drugs from 1981 to 2014. J Nat Prod 2016;79:629–61. https://doi.org/10.1021/acs.jnatprod.5b01055.Search in Google Scholar
3. Cragg, GM, Kingston, DGI, Newman, DJ, editors. Anticancer agents from natural products, 2 ed. Boca Raton, FL: CRC Press/Taylor & Francis; 2012.10.1201/b11185Search in Google Scholar
4. Lee, IC, Choi, BY. WithaferinA-a natural anticancer agent with pleitropic mechanisms of action. Int J Mol Sci 2016;17:290. https://doi.org/10.3390/ijms17030290.Search in Google Scholar
5. Mirmalek, SA, Azizi, MA, Jangholi, E, Yadollah-Damavandi, S, Javidi, MA, Parsa, Y, et al. Cytotoxic and apoptogenic effect of hypericin, the bioactive component of Hypericum perforatum on the MCF-7 human breast cancer cell line. Canc Cell Int 2016;16:3. https://doi.org/10.1186/s12935-016-0279-4.Search in Google Scholar
6. Liu, D, Chen, Z. The effect of curcumin on breast cancer cells. J Breast Cancer 2013;16:133–7. https://doi.org/10.4048/jbc.2013.16.2.133.Search in Google Scholar
7. Rafieian-Kopaei, M, Movahedi, M. Breast cancer chemopreventive and chemotherapeutic effects of Camellia Sinensis (green tea): an updated review. Electron Physician 2017;9:3838–44. https://doi.org/10.19082/3838.Search in Google Scholar
8. Elkady, AI, Abuzinadah, OA, Baeshen, NA, Rahmy, TR. Differential control of growth, apoptotic activity, and gene expression in human breast cancer cells by extracts derived from medicinal herbs Zingiber officinale. J Biomed Biotechnol 2012;2012:614356. https://doi.org/10.1155/2012/614356.Search in Google Scholar
9. Matić, S, Stanić, S, Solujić, S, Milošević, T, Niciforović, N. Biological properties of the Cotinus coggygria methanol extract. Period Biol 2011;113:87–92.Search in Google Scholar
10. Dulger, G, Ince, NK, Caliskan, E, Dulger, B. Anti-yeast properties of the leaves of Cotinus coggygria against clinically relevant fungal pathogens. J Med Plants Stud 2016;4:116–8.Search in Google Scholar
11. Marčetić, M, Božić, D, Milenković, M, Malešević, N, Radulović, S, Kovačević, N. Antimicrobial, antioxidant and anti-inflammatory activity of young shoots of the smoke tree, Cotinus coggygria Scop. Phytother Res 2013;27:1658–63 https://doi.org/10.1002/ptr.4919.Search in Google Scholar
12. Matić, S, Stanić, S, Bogojević, D, Vidaković, M, Grdović, N, Arambašić, J, et al. Extract of the plant Cotinus coggygria Scop. attenuates pyrogallol-induced hepatic oxidative stress in Wistar rats. Can J Physiol Pharmacol 2011;89:401–11 https://doi.org/10.1139/y11-043.Search in Google Scholar
13. Ivanova, D, Gerova, D, Chervenkov, T, Yankova, T. Polyphenols and antioxidant capacity of Bulgarian medicinal plants. J Ethnopharmacol 2005;96:145–50. https://doi.org/10.1016/j.jep.2004.08.033.Search in Google Scholar
14. Savikin, K, Zdunic, G, Jankovic, T, Stanojkovic, T, Juranic, Z, Menković, N. In vitro cytotoxic and antioxidative activity of Cornus mas and Cotinus coggygria. Nat Prod Res 2009;23:1731–9.10.1080/14786410802267650Search in Google Scholar
15. Pollio, A, Zarrelli, A, Romanucci, V, Di Mauro, A, Barra, F, Pinto, G, et al. Polyphenolic profile and targeted bioactivity of methanolic extracts from Mediterranean ethnomedicinal plants on human cancer cell lines. Molecules 2016;21:395. https://doi.org/10.3390/molecules21040395.Search in Google Scholar
16. Artun, FT, Karagoz, A, Ozcan, G, Melikoglu, G, Anil, S, Kultur, S, et al. In vitro anticancer and cytotoxic activities of some plant extracts on HeLa and Vero cell lines. J BUON 2016;21:720–5.10.3390/proceedings1101019Search in Google Scholar
17. Antal, DS, Ardelean, F, Pinzaru, I, Borcan, F, Ledeţi, I, Coricovac, D, et al. Effects of cyclodextrin complexation on the anti-cancer effects of Cotinus coggygria extract and its constituents, butein and sulfuretin. Rev de Chim 2016;67:1618–22.Search in Google Scholar
18. Bozkurt, GÇ, Serbetci, T, Kultur, S. Cytotoxic activities of some Turkish medicinal plants against HeLa cells in vitro. Indian J Tradit Know 2018;17:43–9.Search in Google Scholar
19. Gospodinova, Z, Antov, G, Christova, R, Krasteva, M. Extracts from Tanacetum vulgare L. and Cotinus coggygria Scop. exert a lower in vitro inhibitory effect on normal mammary epithelial cell viability than on breast cancer. In: Anticancer research abstracts of the Ninth International conference of anticancer research. Sithonia, Greece: Anticancer Research; 2014;34:5928 p.Search in Google Scholar
20. Gospodinova, Z, Krasteva, M. Cotinus coggygria Scop. leaf extract exerts high but not dose- and time-dependent in vitro cytotoxic activity on human breast cancer cells. Genet Plant Physiol 2017;7:176–83.Search in Google Scholar
21. Gospodinova, Z, Bózsity, N, Nikolova, M, Krasteva, M, Zupkó, I. Antiproliferative properties against human breast, cervical and ovarian cancer cell lines, and antioxidant capacity of leaf aqueous ethanolic extract from Cotinus coggygria Scop. Acta Med Bulg 2017;44:20–5. https://doi.org/10.1515/amb-2017-0014.Search in Google Scholar
22. Nicoletti, I, Migliorati, G, Pagliacci, MC, Grignani, F, Riccardi, C. A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry. J Immunol Methods 1991;139:271–9. https://doi.org/10.1016/0022-1759(91)90198-o.Search in Google Scholar
23. Georgieva, M, Stoilov, L. Assessment of DNA strand breaks induced by bleomycin in barley by the comet assay. Environ Mol Mutagen 2008;49:381–7. https://doi.org/10.1002/em.20396.Search in Google Scholar
24. Kala, R, Shah, HN, Martin, SL, Tollefsbol, TO. Epigenetic-based combinatorial resveratrol and pterostilbene alters DNA damage response by affecting SIRT1 and DNMT enzyme expression, including SIRT1-dependent γ-H2AX and telomerase regulation in triplenegative breast cancer. BMC Canc 2015;15:672. https://doi.org/10.1186/s12885-015-1693-z.Search in Google Scholar
25. Müller, C, Readhead, C, Diederichs, S, Idos, G, Yang, R, Tidow, N, et al. Methylation of the cyclin A1 promoter correlates with gene silencing in somatic cell lines, while tissue-specific expression of cyclin A1 is methylation independent. Mol Cell Biol 2000;20:3316–29 https://doi.org/10.1128/mcb.20.9.3316-3329.2000.Search in Google Scholar
26. Rubenstein, М, Hollowell, CM, Guinan, P. Increased expression of the androgen receptor with p300 and interleukin-6 coactivators compensate for oligonucleotide suppression of bcl-2: no increased CREB binding protein or interleukin-4 expression. Ther Adv Urol 2013;5:85–93. https://doi.org/10.1177/1756287212466281.Search in Google Scholar
27. Ilyas, A, Hashim, Z, Naeem, N, Haneef, K, Zarina, S. The Effect of alendronate on proteome of hepatocellular carcinoma cell lines. Int J Proteomics 2014;2014:532953, https://doi.org/10.1155/2014/532953.Search in Google Scholar
28. Pfaffl, MW. A new mathematical model for relative quantification in real-time RT–PCR. Nucleic Acids Res 2001;29:e45. https://doi.org/10.1093/nar/29.9.e45.Search in Google Scholar
29. Todinova, SJ, Stoyanova, E, Krumova, SB, Iliev, I, Taneva, SG. Calorimetric signatures of human cancer cells and their nuclei. Thermochim Acta 2016;623:95–101. https://doi.org/10.1016/j.tca.2015.11.002.Search in Google Scholar
30. Wang, G, Wang, J, Du, L, Li, F. Effect and mechanism of total flavonoids extracted from Cotinus coggygria against glioblastoma cancer in vitro and in vivo. BioMed Res Int 2015;2015:856349. https://doi.org/10.1155/2015/856349.Search in Google Scholar
31. Kawada, M, Ohno, Y, Ri, Y, Ikoma, T, Yuugetu, H, Asai, T, et al. Anti-tumor effect of gallic acid on LL-2 lung cancer cells transplanted in mice. Anti Canc Drugs 2001;12:847–52. https://doi.org/10.1097/00001813-200111000-00009.Search in Google Scholar
32. Lee, HL, Lin, CS, Kao, SH, Chou, MC. Gallic acid induces G1 phase arrest and apoptosis of triple-negative breast cancer cell MDA-MB-231 via p38 mitogen-activated protein kinase/p21/p27 axis. Anti Canc Drugs 2017;28:1150–6. https://doi.org/10.1097/cad.0000000000000565.Search in Google Scholar
33. Ruela-de-Sousa, RR, Fuhler, GM, Blom, N, Ferreira, CV, Aoyama, H, Peppelenbosch, MP. Cytotoxicity of apigenin on leukemia cell lines: implications for prevention and therapy. Cell Death Dis 2010;1:e19. https://doi.org/10.1038/cddis.2009.18.Search in Google Scholar
34. Zhang, H, Zhang, M, Yu, L, Zhao, Y, He, N, Yang, X. Antitumor activities of quercetin and quercetin-51,8-disulfonate in human colon and breast cancer cell lines. Food Chem Toxicol 2012;50:1589–99. https://doi.org/10.1016/j.fct.2012.01.025.Search in Google Scholar
35. Rengarajan, T, Yaacob, NS. The flavonoid fisetin as an anticancer agent targeting the growth signaling pathways. Eur J Pharmacol 2016;789:8–16. https://doi.org/10.1016/j.ejphar.2016.07.001.Search in Google Scholar
36. Jung, SK, Lee, MH, Lim, DY, Kim, JE, Singh, P, Lee, SY, et al. Isoliquiritigenin induces apoptosis and inhibits xenograft tumor growth of human lung cancer cells by targeting both wild type and L858R/T790M mutant EGFR. J Biol Chem 2014;289:35839–48. https://doi.org/10.1074/jbc.m114.585513.Search in Google Scholar
37. Lu, J, Papp, LV, Fang, J, Rodriguez-Nieto, S, Zhivotovsky, B, Holmgren, A. Inhibition of mammalian thioredoxin reductase by some flavonoids: implications for myricetin and quercetin anticancer activity. Canc Res 2006;66:4410–8. https://doi.org/10.1158/0008-5472.can-05-3310.Search in Google Scholar
38. Yan, X, Qi, M, Li, P, Zhan, Y, Shao, H. Apigenin in cancer therapy: anti-cancer effects and mechanisms of action. Cell Biosci 2017;7:50. https://doi.org/10.1186/s13578-017-0179-x.Search in Google Scholar
39. Bai, H, Jin, H, Yang, F, Zhu, H, Cai, J. Apigenin induced MCF-7 cell apoptosis-associated reactive oxygen species. Scanning 2014;36:622–31. https://doi.org/10.1002/sca.21170.Search in Google Scholar
40. Vrhovac Madunić, I, Madunić, J, Antunović, M, Paradžik, M, Garaj-Vrhovac, V, Breljak, D, et al. Apigenin, a dietary flavonoid, induces apoptosis, DNA damage, and oxidative stress in human breast cancer MCF-7 and MDA MB-231 cells. Naunyn-Schmiedeberg’s Arch Pharmacol 2018;391:537–50.10.1007/s00210-018-1486-4Search in Google Scholar PubMed
41. Wang, K, Zhu, X, Zhang, K, Zhu, L, Zhou, F. Investigation of gallic acid induced anticancer effect in human breast carcinoma MCF‐7 cells. J Biochem Mol Toxicol 2014;28:387–93. https://doi.org/10.1002/jbt.21575.Search in Google Scholar
42. Hsu, JD, Kao, SH, Ou, TT, Chen, YJ, Li, YJ, Wang, CJ. Gallic acid induces G2/M phase arrest of breast cancer cell MCF-7 through stabilization of p27(Kip1) attributed to disruption of p27(Kip1)/Skp2 complex. J Agric Food Chem 2011;59:1996–2003. https://doi.org/10.1021/jf103656v.Search in Google Scholar
43. Matić, S, Stanić, S, Bogojević, D, Solujić, S, Grdović, N, Vidakovic, M, et al. Genotoxic potential of Cotinus coggygria Scop. (Anacardiaceae) stem extract in vivo. Genet Mol Biol 2011;34:298–303. https://doi.org/10.1590/s1415-47572011005000001.Search in Google Scholar
44. Almagor, M, Cole, RD. Differential scanning calorimetry of nuclei as a test for the effects of anticancer drugs on human chromatin. Canc Res 1989;49:5561–6.Search in Google Scholar
45. Góralski, P, Rogalińska, M, Błoński, JZ, Pytel, E, Robak, T, Kiliańska, ZM, et al. The differences in thermal profiles between normal and leukemic cells exposed to anticancer drug evaluated by differential scanning calorimetry. J Therm Anal Calorim 2014;118:1339–44. https://doi.org/10.1007/s10973-014-3957-2.Search in Google Scholar
46. Hendrich, B, Bird, A. Mammalian methyltransferases and methyl-CpG-binding domains: proteins involved in DNA methylation. Curr Top Microbiol Immunol 2000;249:55–74. https://doi.org/10.1007/978-3-642-59696-4_4.Search in Google Scholar
47. Hendrich, B, Bird, A. Identification and characterization of a family of mammalian methyl-CpG binding proteins. Mol Cell Biol 1998;18:6538–47. https://doi.org/10.1128/mcb.18.11.6538.Search in Google Scholar
48. Probst, AV, Dunleavy, E, Almouzni, G. Epigenetic inheritance during the cell cycle. Nat Rev Mol Cell Biol 2009;10:192–206. https://doi.org/10.1038/nrm2640.Search in Google Scholar
49. Yildirim, O, Li, R, Hung, JH, Chen, PB, Dong, X, Ee, LS, et al. Mbd3/NURD complex regulates expression of 5-hydroxymethylcytosine marked genes in embryonic stem cells. Cell 2011;147:1498–510. https://doi.org/10.1016/j.cell.2011.11.054.Search in Google Scholar
50. Sterner, DE, Berger, S. Acetylation of histones and transcription-related factors. Microbiol Mol Biol Rev 2000;64:435–59. https://doi.org/10.1128/mmbr.64.2.435-459.2000.Search in Google Scholar
51. Tunca, B, Tezcan, G, Cecener, G, Egeli, U, Ak, S, Malyer, H, et al. Olea europaea leaf extract alters microRNA expression in human glioblastoma cells. J Canc Res Clin Oncol 2012;138:1831–44. https://doi.org/10.1007/s00432-012-1261-8.Search in Google Scholar
52. Jha, AK, Nikbakht, M, Capalash, N, Kaur, J. Demethylation of RARβ2 gene promoter by Withania somnifera in HeLa cell line. Eur J Med Plants 2014;4:503–10. https://doi.org/10.9734/ejmp/2014/5975.Search in Google Scholar
53. Hardy, TM, Tollefsbol, TO. Epigenetic diet: impact on the epigenome and cancer. Epigenomics 2011;3:503–18. https://doi.org/10.2217/epi.11.71.Search in Google Scholar
54. Thakur, VS, Deb, G, Babcook, MA, Gupta, S. Plant phytochemicals as epigenetic modulators: role in cancer chemoprevention. AAPS J 2014;16:151–63. https://doi.org/10.1208/s12248-013-9548-5.Search in Google Scholar
55. Fang, M, Chen, D, Yang, CS. Dietary polyphenols may affect DNA methylation. J Nutr 2007;137:223S–8S. https://doi.org/10.1093/jn/137.1.223s.Search in Google Scholar
56. Pandey, M, Kaur, P, Shukla, S, Abbas, A, Fu, P, Gupta, S. Plant flavone apigenin inhibits HDAC and remodels chromatin to induce growth arrest and apoptosis in human prostate cancer cells: in vitro and in vivo study. Mol Carcinog 2012;51:952–62. https://doi.org/10.1002/mc.20866.Search in Google Scholar
57. Choi, KC, Lee, YH, Jung, MG, Kwon, SH, Kim, MJ, Jun, WJ, et al. Gallic acid suppresses lipopolysaccharide-induced nuclear factor-kappaB signaling by preventing RelA acetylation in A549 lung cancer cells. Mol Canc Res 2009;7:2011–21. https://doi.org/10.1158/1541-7786.mcr-09-0239.Search in Google Scholar
58. Weng, YP, Hung, PF, Ku, WY, Chang, CY, Wu, BH, Wu, MH, et al. The inhibitory activity of gallic acid against DNA methylation: application of gallic acid on epigenetic therapy of human cancers. Oncotarget 2018;9:361–74. https://doi.org/10.18632/oncotarget.23015.Search in Google Scholar
59. Gospodinova, Z, Krasteva, M, Manova, V. Effects of Cotinus coggygria extract on the transcriptional levels of histone deacetylase genes in breast cancer cells in vitro. Am J Pharm Health Res 2017;5:60–9.Search in Google Scholar
© 2020 Walter de Gruyter GmbH, Berlin/Boston
