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Antiproliferative and apoptotic effects of caffeic acid on SK-Mel-28 human melanoma cancer cells

  • Luana Paula Pelinson
  • Charles Elias Assmann
  • Taís Vidal Palma
  • Ivana Beatrice Mânica da Cruz
  • Micheli Mainardi Pillat
  • Aline Mânica
  • Naiara Stefanello
  • Grazielle Castagna Cezimbra Weis
  • Audrei de Oliveira Alves
  • Cinthia Melazzo de Andrade
  • Henning Ulrich
  • Vera Maria Melchiors Morsch
  • Maria Rosa Chitolina Schetinger
  • Margarete Dulce BagatiniEmail author
Original Article
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Abstract

Cutaneous melanoma (CM) is an extremely aggressive cancer presenting low survival and high mortality. The vast majority of patients affected by this disease does not respond or show resistance to the chemotherapeutic drugs, which makes the treatment ineffective. In this sense, the necessity for the development of new agents to assist in CM therapy is extremely important. One of the sources of great interest in this search are compounds of natural origin. Among these compounds, caffeic acid has demonstrated a broad spectrum of pharmacological activities as well as antitumor effects in some types of cancer. Therefore, the objective of this work was to investigate the possible antitumor effect of caffeic acid on the SK-Mel-28 cell line, human CM cells. Cells were cultured in flasks with culture medium containing fetal bovine serum, antibiotic, and antifungal, and maintained in ideal conditions. Cells were treated with 25 µM, 50 µM, 100 µM, 150 µM and 200 µM of caffeic acid and dacarbazine at 1 mg/mL. We verified the effect on cell viability and cell death, apoptosis, cell cycle, colony formation and gene expression of caspases. Results showed a decrease in cell viability, cell death induction by apoptosis, inhibition of colony formation, modulation of cell cycle and alterations in gene expression of caspases after caffeic acid treatment. These results suggest an antitumor effect of the compound on SK-Mel-28 cells. This study provides original information on mechanisms by which caffeic acid may play a key role in preventing tumor progression in human melanoma cells.

Keywords

Melanoma Natural compounds Cytotoxicity Apoptosis Cell cycle Gene expression 

Notes

Funding

The authors would like to thank the financial support of CAPES [CAPES/PROEX—Process Numbers: 23038.005848/2018-31 and 88882.182142/2018-01] and CNPq [MDB Project. No. 449485/2014-5], Brazil. Funding sources are non-profit governmental agencies and had no role in study design, in the collection, analysis, and interpretation of the data, in the writing of the manuscript, and in the decision for publication.

Compliance with ethical standards

Conflict of interest

The authors declare that they no conflicts of interest.

Ethical approval

All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Informed consent

Infromed consent was obtained from all individual participants in the study.

References

  1. 1.
    O’Sullivan J, O’Connor D (2018) The modern approach to targeting melanoma. In: Human skin cancers—pathways, mechanisms, targets and treatments. InTechOpen, LondonGoogle Scholar
  2. 2.
    Akbani R, Akdemir KC, Aksoy BA et al (2015) Genomic classification of cutaneous melanoma. Cell 161:1681–1696CrossRefGoogle Scholar
  3. 3.
    Garbe C, Eigentler TK, Keilholz U, Hauschild A, Kirkwood JM (2011) Systematic review of medical treatment in melanoma: current status and future prospects. Oncologist 16:5–24CrossRefGoogle Scholar
  4. 4.
    Gogas HJ, Kirkwood JM, Sondak VK (2007) Chemotherapy for metastatic melanoma: time for a change? Cancer 109:455–464CrossRefGoogle Scholar
  5. 5.
    Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S, Gore M, Aamdal S, Cebon J, Coates A, Dreno B, Henz M, Schadendorf D, Kapp A, Weiss J, Fraass U, Statkevich P, Muller M, Thatcher N (2000) Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol 18:158–166CrossRefGoogle Scholar
  6. 6.
    Sanlorenzo M, Vujic I, Posch C, Dajee A, Yen A, Kim S, Ashworth M, Rosenblum MD, Algazi A, Osella-Abate S, Quaglino P, Daud A, Ortiz-Urda S (2014) Melanoma immunotherapy. Cancer Biol Ther 15:665–674CrossRefGoogle Scholar
  7. 7.
    Franklin C, Livingstone E, Roesch A, Schilling B, Schadendorf D (2017) Immunotherapy in melanoma: recent advances and future directions. Eur J Surg Oncol 43:604–611CrossRefGoogle Scholar
  8. 8.
    Tapiero H, Tew K, Nguyen Ba G, Mathé G (2002) Polyphenols: do they play a role in the prevention of human pathologies? Biomed Pharmacother 56:200–207CrossRefGoogle Scholar
  9. 9.
    Shi J, Yu J, Pohorly JE, Kakuda Y (2003) Polyphenolics in grape seeds-biochemistry and functionality. J Med Food 6:291–299CrossRefGoogle Scholar
  10. 10.
    Weng CJ, Yen GC (2012) Chemopreventive effects of dietary phytochemicals against cancer invasion and metastasis: phenolic acids, monophenol, polyphenol, and their derivatives. Cancer Treat Rev 38:76–87CrossRefGoogle Scholar
  11. 11.
    Jaganathan SK (2012) Growth inhibition by caffeic acid, one of the phenolic constituents of honey, in HCT 15 colon cancer cells. Sci World J 2012:372345CrossRefGoogle Scholar
  12. 12.
    Assmann CE, Cadoná FC, Bonadiman BDSR, Dornelles EB, Trevisan G, Cruz IBMD (2018) Tea tree oil presents in vitro antitumor activity on breast cancer cells without cytotoxic effects on fibroblasts and on peripheral blood mononuclear cells. Biomed Pharmacother 103:1253–1261CrossRefGoogle Scholar
  13. 13.
    Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63CrossRefGoogle Scholar
  14. 14.
    Konopka K, Pretzer E, Felgner PL, Düzgüneş N (1996) Human immunodeficiency virus type-1 (HIV-1) infection increases the sensitivity of macrophages and THP-1 cells to cytotoxicity by cationic liposomes. Biochim Biophys Acta 1312:186–196CrossRefGoogle Scholar
  15. 15.
    Vermes I, Haanen C, Steffens-Nakken H, Reutellingsperger C (1995) A novel assay for apoptosis flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled annexin V. J Immunol Methods 184:39–51CrossRefGoogle Scholar
  16. 16.
    da Silva LM, Frión-Herrera Y, Bartolomeu AR, Gorgulho CM, Sforcin JM (2017) Mechanisms involved in the cytotoxic action of Brazilian propolis and caffeic acid against HEp-2 cells and modulation of P-glycoprotein activity. J Pharm Pharmacol 69:1625–1633CrossRefGoogle Scholar
  17. 17.
    Cubillos-Rojas M, Amair-Pinedo F, Peiró-Jordán R, Bartrons R, Ventura F, Rosa JL (2014) The E3 ubiquitin protein ligase HERC2 modulates the activity of tumor protein p53 by regulating its oligomerization. J Biol Chem 289:14782–14795CrossRefGoogle Scholar
  18. 18.
    Kampa M, Alexaki V, Notas G, Nifli AP, Nistikaki A, Hatzoglou A, Bakogeorgou E, Kouimtzoglou E, Blekas G, Boskou D, Gravanis A, Castanas E (2004) Antiproliferative and apoptotic effects of selective phenolic acids on T47D human breast cancer cells: potential mechanisms of action. Breast Cancer Res 6:R63–R74CrossRefGoogle Scholar
  19. 19.
    Takahashi H, Nguyen BCQ, Uto Y, Shahinozzaman M, Tawata S, Maruta H (2017) 1,2,3-Triazolyl esterization of PAK1-blocking propolis ingredients, artepillin C (ARC) and caffeic acid (CA), for boosting their anti-cancer/anti-PAK1 activities along with cell-permeability. Drug Discov Ther 11:104–109CrossRefGoogle Scholar
  20. 20.
    Chang WC, Hsieh CH, Hsiao MW, Lin WC, Hung YC, Ye JC (2010) Caffeic acid induces apoptosis in human cervical cancer cells through the mitochondrial pathway. Taiwan J Obstet Gynecol 49:419–424CrossRefGoogle Scholar
  21. 21.
    Huang W, Seo J, Willingham SB, Czyzewski AM, Gonzalgo ML, Weissman IL, Barron AE (2014) Learning from host-defense peptides: cationic, amphipathic peptoids with potent anticancer activity. PLoS ONE 9:e90397CrossRefGoogle Scholar
  22. 22.
    Mulder KC, Lima LA, Miranda VJ, Dias SC, Franco OL (2013) Current scenario of peptide-based drugs: the key roles of cationic antitumor and antiviral peptides. Front Microbiol 4:321CrossRefGoogle Scholar
  23. 23.
    Búfalo MC, Sforcin JM (2015) The modulatory effects of caffeic acid on human monocytes and its involvement in propolis action. J Pharm Pharmacol 67:740–745CrossRefGoogle Scholar
  24. 24.
    Kilani-Jaziri S, Mokdad-Bzeouich I, Krifa M, Nasr N, Ghedira K, Chekir-Ghedira L (2017) Immunomodulatory and cellular anti-oxidant activities of caffeic, ferulic, and p-coumaric phenolic acids: a structure-activity relationship study. Drug Chem Toxicol 40:416–424CrossRefGoogle Scholar
  25. 25.
    Murad LD, Soares Nda C, Brand C, Monteiro MC, Teodoro AJ (2015) Effects of caffeic and 5-caffeoylquinic acids on cell viability and cellular uptake in human colon adenocarcinoma cells. Nutr Cancer 67:532–542CrossRefGoogle Scholar
  26. 26.
    Chen YN (2017) Dacarbazine inhibits proliferation of melanoma FEMX-1 cells by up-regulating expression of miRNA-200. Eur Rev Med Pharmacol Sci 21:1191–1197Google Scholar
  27. 27.
    Baharara J, Amini E, Nikdel N, Salek-Abdollahi F (2016) The cytotoxicity of dacarbazine potentiated by sea cucumber saponin in resistant B16F10 melanoma cells through apoptosis induction. Avicenna J Med Biotechnol 8:112–119Google Scholar
  28. 28.
    He J, Xu Q, Jing Y, Agani F, Qian X, Carpenter R, Li Q, Wang XR, Peiper SS, Lu Z, Liu LZ, Jiang BH (2012) Reactive oxygen species regulate ERBB2 and ERBB3 expression via miR-199a/125b and DNA methylation. EMBO Rep 13:1116–1122CrossRefGoogle Scholar
  29. 29.
    Grabsch H, Takeno S, Parsons WJ, Pomjanski N, Boecking A, Gabbert HE, Mueller W (2003) Overexpression of the mitotic checkpoint genes BUB1, BUBR1, and BUB3 in gastric cancer-association with tumour cell proliferation. J Pathol 200:16–22CrossRefGoogle Scholar
  30. 30.
    Pinto M, Vieira J, Ribeiro FR, Soares MJ, Henrique R, Oliveira J, Jerónimo C, Teixeira MR (2008) Overexpression of the mitotic checkpoint genes BUB1 and BUBR1 is associated with genomic complexity in clear cell kidney carcinomas. Cell Oncol 30:389–395Google Scholar
  31. 31.
    Burum-Auensen E, DeAngelis PM, Schjølberg AR, Røislien J, Mjåland O, Clausen OP (2008) Reduced level of the spindle checkpoint protein BUB1B is associated with aneuploidy in colorectal cancers. Cell Prolif 41:645–659CrossRefGoogle Scholar
  32. 32.
    Kato T, Daigo Y, Aragaki M, Ishikawa K, Sato M, Kondo S, Kaji M (2011) Overexpression of MAD2 predicts clinical outcome in primary lung cancer patients. Lung Cancer 74:124–131CrossRefGoogle Scholar
  33. 33.
    Min J, Shen H, Xi W, Wang Q, Yin L, Zhang Y, Yu Y, Yang Q, Wang ZN (2018) Synergistic anticancer activity of combined use of caffeic acid with paclitaxel enhances apoptosis of non-small-cell lung cancer H1299 cells in vivo and in vitro. Cell Physiol Biochem 48:1433–1442CrossRefGoogle Scholar
  34. 34.
    Dziedzic A, Kubina R, Kabała-Dzik A, Tanasiewicz M (2017) Induction of cell cycle arrest and apoptotic response of head and neck squamous carcinoma cells (Detroit 562) by caffeic acid and caffeic acid phenethyl ester derivative. Evid Based Complement Altern Med 2017:6793456CrossRefGoogle Scholar
  35. 35.
    Kabała-Dzik A, Rzepecka-Stojko A, Kubina R, Jastrzębska-Stojko Ż, Stojko R, Wojtyczka RD, Stojko J (2017) Comparison of two components of propolis: caffeic acid (CA) and caffeic acid phenethyl ester (CAPE) induce apoptosis and cell cycle arrest of breast cancer cells MDA-MB-231. Molecules 22:E1554CrossRefGoogle Scholar
  36. 36.
    Sadeghi Ekbatan S, Li XQ, Ghorbani M, Azadi B, Kubow S (2018) Chlorogenic acid and its microbial metabolites exert anti-proliferative effects, S-phase cell-cycle arrest and apoptosis in human colon cancer caco-2 cells. Int J Mol Sci 19:E723CrossRefGoogle Scholar
  37. 37.
    Gokbulut AA, Apohan E, Baran Y (2013) Resveratrol and quercetin-induced apoptosis of human 232B4 chronic lymphocytic leukemia cells by activation of caspase-3 and cell cycle arrest. Hematology 18:144–150CrossRefGoogle Scholar
  38. 38.
    Munshi A, Hobbs M, Meyn RE (2005) Clonogenic cell survival assay. Methods Mol Med 110:21–28Google Scholar
  39. 39.
    Kudugunti SK, Vad NM, Ekogbo E, Moridani MY (2011) Efficacy of caffeic acid phenethyl ester (CAPE) in skin B16-F0 melanoma tumor bearing C57BL/6 mice. Investig N Drugs 29:52–62CrossRefGoogle Scholar
  40. 40.
    Pramanik KC, Kudugunti SK, Fofaria NM, Moridani MY, Srivastava SK (2013) Caffeic acid phenethyl ester suppresses melanoma tumor growth by inhibiting PI3K/AKT/XIAP pathway. Carcinogenesis 34:2061–2070CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  • Luana Paula Pelinson
    • 1
  • Charles Elias Assmann
    • 1
  • Taís Vidal Palma
    • 2
  • Ivana Beatrice Mânica da Cruz
    • 3
  • Micheli Mainardi Pillat
    • 4
  • Aline Mânica
    • 1
  • Naiara Stefanello
    • 1
  • Grazielle Castagna Cezimbra Weis
    • 3
  • Audrei de Oliveira Alves
    • 3
  • Cinthia Melazzo de Andrade
    • 2
  • Henning Ulrich
    • 4
  • Vera Maria Melchiors Morsch
    • 1
  • Maria Rosa Chitolina Schetinger
    • 1
  • Margarete Dulce Bagatini
    • 1
    • 5
    Email author
  1. 1.PPGBtox, CCNEFederal University of Santa MariaSanta MariaBrazil
  2. 2.Laboratory of Oxidative BiochemistryFederal University of Santa MariaSanta MariaBrazil
  3. 3.Laboratory of BiogenomicsFederal University of Santa MariaSanta MariaBrazil
  4. 4.Department of Biochemistry, Institute of ChemistryUniversity of São PauloSão PauloBrazil
  5. 5.Academic Coordination, Federal University of Fronteira SulChapecóBrazil

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