CC BY-NC-ND 4.0 · Planta Medica International Open 2022; 9(01): e34-e53
DOI: 10.1055/a-1623-2938
Original Papers

Tea Tree Oil and Terpinen-4-Ol Induce Cytoskeletal Reorganization of Human Melanoma Cells

Giuseppina Bozzuto
1   Centro Nazionale per la Ricerca e la Valutazione preclinica e clinica dei Farmaci, Istituto Superiore di Sanità, Rome, Italy
,
Fulvia Mariano
1   Centro Nazionale per la Ricerca e la Valutazione preclinica e clinica dei Farmaci, Istituto Superiore di Sanità, Rome, Italy
,
Ilaria Costa
2   Leica Microsystems S.r.l, Buccinasco, Milano, Italy
,
Annarica Calcabrini
1   Centro Nazionale per la Ricerca e la Valutazione preclinica e clinica dei Farmaci, Istituto Superiore di Sanità, Rome, Italy
,
Agnese Molinari
1   Centro Nazionale per la Ricerca e la Valutazione preclinica e clinica dei Farmaci, Istituto Superiore di Sanità, Rome, Italy
› Author Affiliations

Abstract

Tea tree oil is an essential oil distilled from the leaves of Melaleuca alternifolia, a plant native to Australia. It has been used in traditional medicine for its antiseptic and anti-inflammatory properties to treat various skin conditions and infections. It has also been incorporated into many topical formulations to treat cutaneous infections and speed wound healing. In vivo and in vitro studies report antiproliferative effects in skin disorders but the molecular mechanisms underlying this effect remain to be still elucidated. In this study MTT assay, scanning electron microscopy-field emission gun, flow cytometry, cell cycle assays, and laser scanning confocal microscopy were utilized to investigate a novel mechanism underlying the antiproliferative effects of tea tree oil and terpinen-4-ol on transformed skin (melanoma) M14 cells. The analysis of the actin cytoskeleton by laser scanning confocal microscopy evidenced a clear action of both essential oil and its main active component on F-actin, which interfered with bundling of actin microfilaments in stress fibers. As for the microtubular network, both tea tree oil and terpinen-4-ol induced a disorganization of the perinuclear cage with the rupture and collapse of microtubules. Finally, they noticeably changed the intermediate filaments architecture by inducing the formation of large vimentin cables. Results obtained in the present study point to the cytoskeleton as a further target of tea tree oil and terpinen-4-ol and could account for the inhibition of proliferation and invasion of skin transformed M14 cells. In our experimental conditions, vimentin intermediate filaments appear to be the cytoskeletal element more affected by the treatments. Moreover, the role of cross-linker proteins in the mechanism of action of tea tree oil has been discussed.

Supplementary Material



Publication History

Received: 16 November 2020
Received: 15 June 2021

Accepted: 11 August 2021

Article published online:
07 February 2022

© 2022. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 Carson CF, Hammer KA, Riley TV. Melaleuca alternifolia (Tea Tree) oil: a review of antimicrobial and other medicinal properties. Clin Microbiol Rev 2006; 19: 50-62
  • 2 Flores FC, De Lima JA, Da Silva CR, Benvegnú D, Ferreira J, Burger ME. , Beck RC, Rolim CM, Rocha MI, Da Veiga ML, Da Silva Cde B. Hydrogels containing nanocapsules and nanoemulsions of tea tree oil provide antiedematogenic effect and improved skin wound healing. J Nanosci Nanotechnol 2015; 15: 800-809
  • 3 Hadaś E, Derda M, Cholewiński M. Evaluation of the effectiveness of tea tree oil in treatment of Acanthamoeba infection. Parasitol Res 2017; 116: 997-1001
  • 4 Labib RM, Ayoub IM, Michel HE, Mehanny M, Kamil V, Hany M. , Magdy M, Moataz A, Maged B, Mohamed A. Appraisal on the wound healing potential of Melaleuca alternifolia and Rosmarinus officinalis L. essential oil-loaded chitosan topical preparations. PLoS One 2019; 14: e0219561
  • 5 Malhi HK, Tu J, Riley TV, Kumarasinghe SP, Hammer KA. Tea tree oil gel for mild to moderate acne; a 12 week uncontrolled, open-label phase II pilot study. Australas J Dermatol 2017; 58: 205-210
  • 6 Mazzarello V, Donadu MG, Ferrari M, Piga G, Usai D, Zanetti S. , Sotgiu MA. Treatment of acne with a combination of propolis, tea tree oil, and aloe vera compared to erythromycin cream: two double-blind investigations. Clin Pharmacol Adv Appl 2018; 10: 175-181
  • 7 Messager S, Hammer KA, Carson CF, Riley TV. Effectiveness of hand-cleansing formulations containing tea tree oil assessed ex vivo on human skin and in vivo with volunteers using European standard EN 1499. J Hosp Infect 2005; 59: 220-228
  • 8 Rothenberger J, Krauss S, Tschumi C, Rahmanian-Schwarz A, Schaller H-. , Held M. The Effect of Polyhexanide, Octenidine Dihydrochloride, and Tea Tree Oil as Topical Antiseptic Agents on In Vivo Microcirculation of the Human Skin: A Noninvasive Quantitative Analysis. Wounds 2016; 28: 341-346
  • 9 Assmann CE, Cadoná FC, Bonadiman BDSR, Dornelles EB, Trevisan G, Cruz IBMD. 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 2018; 103: 1253-1261
  • 10 Banjerdpongchai R, Khaw-On P. Terpinen-4-ol induces autophagic and apoptotic cell death in human leukemic HL-60 cells. Asian Pac J Cancer Preven 2013; 14: 7537-7542
  • 11 Calcabrini A, Stringaro A, Toccacieli L, Meschini S, Marra M, Colone M. Salvatore G, Mondello F, Arancia G, Molinari A. Terpinen-4-ol, the main component of Melaleuca alternifolia (tea tree) oil inhibits the in vitro growth of human melanoma cells. J Invest Dermatol 2004; 122: 349-360
  • 12 Greay SJ, Ireland DJ, Kissick HT, Levy A, Beilharz MW, Riley TV. Carson CF. Induction of necrosis and cell cycle arrest in murine cancer cell lines by Melaleuca alternifolia (tea tree) oil and terpinen-4-ol. Cancer Chemother Pharmacol 2010; 65: 877-888
  • 13 Khaw-on P, Banjerdpongchai R. Induction of intrinsic and extrinsic apoptosis pathways in the human leukemic MOLT-4 cell line by terpinen-4-ol. Asian Pac J Cancer Preven 2012; 13: 3073-3076
  • 14 Ramadan MA, Shawkey AE, Rabeh MA, Abdellatif AO. Expression of P53, BAX, and BCL-2 in human malignant melanoma and squamous cell carcinoma cells after tea tree oil treatment in vitro . Cytotechnology 2019; 71: 461-473
  • 15 Greay SJ, Ireland DJ, Kissick HT, Heenan PJ, Carson CF, Riley TV. Beilharz MW. Inhibition of established subcutaneous murine tumour growth with topical Melaleuca alternifolia (tea tree) oil. Cancer Chemother Pharmacol 2010; 66: 1095-1102
  • 16 Ireland DJ, Greay SJ, Hooper CM, Kissick HT, Filion P, Riley TV. Beilharz MW. Topically applied Melaleuca alternifolia (tea tree) oil causes direct anti-cancer cytotoxicity in subcutaneous tumour bearing mice. J Dermatol Sci 2012; 67: 120-129
  • 17 Shapira S, Pleban S, Kazanov D, Tirosh P, Arber N. Terpinen-4-ol: A Novel and Promising Therapeutic Agent for Human Gastrointestinal Cancers. PLoS One 2016; 11: e0156540
  • 18 Giordani C, Molinari A, Toccacieli L, Calcabrini A, Stringaro A, Chistolini P. Arancia G, Diociaiuti M. Interaction of tea tree oil with model and cellular membranes. J Med Chem 2006; 49: 4581-4588
  • 19 Colone M, Calcabrini A, Toccacieli L, Bozzuto G, Stringaro A, Gentile M. Cianfriglia M, Ciervo A, Caraglia M, Budillon A, Meo G, Arancia G, Molinari A. The multidrug transporter P-glycoprotein: a mediator of melanoma invasion?. J Invest Dermatol 2008; 128: 957-971
  • 20 Bozzuto G, Colone M, Toccacieli L, Stringaro A, Molinari A. Tea tree oil might combat melanoma. Planta Med 2011; 77: 54-56
  • 21 Strouhalova K, Přechová M, Gandalovičová A, Brábek J, Gregor M, Rosel D. Vimentin intermediate filaments as potential target for cancer treatment. Cancers 2020; 12: 184
  • 22 Hall A. The cytoskeleton and cancer. Cancer Metastasis Rev 2009; 28: 5-14
  • 23 Hohmann T, Dehghani F. The Cytoskeleton-A Complex Interacting Meshwork. Cells 2019; 8: 362
  • 24 Wen Q, Janmey PA. Polymer physics of the cytoskeleton. Curr Opin Solid State Mater Sci 2011; 15: 177-182
  • 25 Bershadsky AD, Balaban NQ, Geiger B. Adhesion-dependent cell mechanosensitivity. Annu Rev Cell Dev Biol 2003; 19: 677-695
  • 26 Geiger B, Bershadsky A, Pankov R, Yamada KM. Transmembrane extracellular matrix-cytoskeleton crosstalk. Nat Rev Mol Cell Biol 2001; 2: 793-805
  • 27 Hotulainen P, Lappalainen P. Stress fibers are generated by two distinct actin assembly mechanisms in motile cells. J Cell Biol 2006; 173: 383-394
  • 28 Livne A, Geiger B. The inner workings of stress fibers - from contractile machinery to focal adhesions and back. J Cell Sci 2016; 129: 1293-1304
  • 29 Gan Z, Ding L, Burckhardt CJ, Lowery J, Zaritsky A, Sitterley K. Mota A, Costigliola N, Starker CG, Voytas DF, Tytell J, Goldman RD, Danuser G. Vimentin Intermediate Filaments Template Microtubule Networks to Enhance Persistence in Cell Polarity and Directed Migration. Cell Syst 2016; 3: 252-263.e8
  • 30 Seetharaman S, Etienne-Manneville S. Microtubules at focal adhesions - a double-edged sword. J Cell Sci 2019; 132: jcs232843
  • 31 Tsuruta D, Jones JCR. The vimentin cytoskeleton regulates focal contact size and adhesion of endothelial cells subjected to shear stress. J Cell Sci 2003; 116: 4977-4984
  • 32 Mellad JA, Warren DT, Shanahan CM. Nesprins LINC the nucleus and cytoskeleton. Curr Opin Cell Biol 2011; 23: 47-54
  • 33 Ketema M, Sonnenberg A. Nesprin-3: a versatile connector between the nucleus and the cytoskeleton. Biochem Soc Trans 2011; 39: 1719-1724
  • 34 Starr DA, Fridolfsson HN. Interactions between nuclei and the cytoskeleton are mediated by SUN-KASH nuclear-envelope bridges. Annu Rev Cell Dev Biol 2010; 26: 421-444
  • 35 Svitkina TM, Verkhovsky AB, Borisy GG. Plectin sidearms mediate interaction of intermediate filaments with microtubules and other components of the cytoskeleton. J Cell Biol 1996; 135: 991-1007
  • 36 Battaglia RA, Delic S, Herrmann H, Snider NT. Vimentin on the move: new developments in cell migration. F1000Res 2018; 7: F1000 Faculty Rev-1796
  • 37 Esue O, Carson AA, Tseng Y, Wirtz D. A direct interaction between actin and vimentin filaments mediated by the tail domain of vimentin. J Biol Chem 2006; 281: 30393-30399
  • 38 Jiu Y, Lehtimäki J, Tojkander S, Cheng F, Jäälinoja H, Liu X. Varjosalo M, Eriksson JE, Lappalainen P. Bidirectional interplay between vimentin intermediate filaments and contractile actin stress fibers. Cell Rep 2015; 11: 1511-1518
  • 39 Sakamoto Y, Boëda B, Etienne-Manneville S. APC binds intermediate filaments and is required for their reorganization during cell migration. J Cell Biol 2013; 200: 249-458