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Anticancer activity of monoterpenes: a systematic review

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Abstract

Secondary metabolites have been recognized for centuries as medicinal agents, in particular monoterpenes which have been the target of research in the discovery of antineoplastic drugs, as they have potential antitumor effect and low toxicity and are used as additives in foods and cosmetics. Another advantage of monoterpenes is structural diversity, which gives greater plasticity when interacting with cells. The purpose of this review was to summarize and critically discuss the anticancer potential of monoterpenes and their respective mechanisms of action. A systematic review of articles in the MEDLINE/PubMed, Web of Science, Scopus and Science Direct electronic databases was independently conducted by three reviewers using the combination of the following keywords: monoterpenes AND anticancer AND in vitro. Restriction in selecting articles followed pre-established inclusion and exclusion criteria by the reviewers, and also a time limitation with works published between 2015 and 2019 being selected. In total, 39 works were deemed eligible for inclusion in the final review. Monoterpenes have cytotoxic activity in a wide variety of tumor cell lines, and mainly appear to exert this effect by inducing apoptosis caused by oxidative stress. In addition, improved use of monoterpenes when used in drug delivery systems and the synergistic effect with conventional chemotherapeutic drugs are reported. These findings validate this class of compounds as a promising source of chemotherapeutic drugs yet to be explored.

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The authors declare that all data supporting the conclusion of this study are available in the article itself.

References

  1. Bray F, Ferlay J, Soerjomataram I et al (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394–424. https://doi.org/10.3322/caac.21492

    Article  PubMed  Google Scholar 

  2. Oturanel CE, Kıran İ, Özşen Ö et al (2017) Cytotoxic, antiproliferative and apoptotic effects of perillyl alcohol and its biotransformation metabolite on A549 and HepG2 cancer cell lines. Anticancer Agents Med Chem 17:1243–1250. https://doi.org/10.2174/1871520617666170103093923

    Article  CAS  PubMed  Google Scholar 

  3. Shrestha S, Song YW, Kim H et al (2016) Sageone, a diterpene from Rosmarinus officinalis, synergizes with cisplatin cytotoxicity in SNU-1 human gastric cancer cells. Phytomedicine 23:1671–1679. https://doi.org/10.1016/j.phymed.2016.09.008

    Article  CAS  PubMed  Google Scholar 

  4. Deb DD, Parimala G, Saravana Devi S, Chakraborty T (2011) Effect of thymol on peripheral blood mononuclear cell PBMC and acute promyelotic cancer cell line HL-60. Chem Biol Interact 193:97–106. https://doi.org/10.1016/j.cbi.2011.05.009

    Article  CAS  PubMed  Google Scholar 

  5. Brahmkshatriya PP, Brahmkshatriya PS (2013) Terpenes: chemistry, biological role, and therapeutic applications. In: Ramawat KG, Mérillon JM (eds) Natural products: phytochemistry, botany and metabolism of alkaloids, phenolics and terpenes. Springer, New York, pp 2665–2691

    Chapter  Google Scholar 

  6. Nikolić B, Vasilijević B, Mitić-Ćulafić D et al (2015) Comparative study of genotoxic, antigenotoxic and cytotoxic activities of monoterpenes camphor, eucalyptol and thujone in bacteria and mammalian cells. Chem Biol Interact 242:263–271. https://doi.org/10.1016/j.cbi.2015.10.012

    Article  CAS  PubMed  Google Scholar 

  7. Aydın E, Turkez H, Tasdemir S, Hacımuftuoglu F (2016) Anticancer, antioxidant and cytotoxic potential of thymol in vitro brain tumor cell model. Cent Nerv Syst Agents Med Chem 17:116–122. https://doi.org/10.2174/1871524916666160823121854

    Article  CAS  Google Scholar 

  8. Zielińska A, Martins-Gomes C, Ferreira NR et al (2018) Anti-inflammatory and anti-cancer activity of citral: optimization of citral-loaded solid lipid nanoparticles (SLN) using experimental factorial design and LUMiSizer®. Int J Pharm 553:428–440. https://doi.org/10.1016/j.ijpharm.2018.10.065

    Article  CAS  PubMed  Google Scholar 

  9. Greay SJ, Hammer KA (2015) Recent developments in the bioactivity of mono- and diterpenes: anticancer and antimicrobial activity. Phytochem Rev. https://doi.org/10.1007/s11101-011-9212-6

    Article  Google Scholar 

  10. Kalalinia F, Karimi-Sani I (2017) Anticancer properties of solamargine: a systematic review. Phyther Res 31:858–870. https://doi.org/10.1002/ptr.5809

    Article  CAS  Google Scholar 

  11. Moura FA, de Andrade KQ, dos Santos JCF et al (2015) Antioxidant therapy for treatment of inflammatory bowel disease: does it work? Redox Biol 6:617–639. https://doi.org/10.1016/j.redox.2015.10.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Montana M, Mathias F, Terme T, Vanelle P (2019) Antitumoral activity of quinoxaline derivatives: a systematic review. Eur J Med Chem 163:136–147. https://doi.org/10.1016/j.ejmech.2018.11.059

    Article  CAS  PubMed  Google Scholar 

  13. Liu S, Zhao Y, Cui HF et al (2016) 4-Terpineol exhibits potent in vitro and in vivo anticancer effects in Hep-G2 hepatocellular carcinoma cells by suppressing cell migration and inducing apoptosis and sub-Gl cell cycle arrest. J BUON 21:1195–1202

    PubMed  Google Scholar 

  14. Pudełek M, Catapano J, Kochanowski P et al (2019) Therapeutic potential of monoterpene α-thujone, the main compound of Thuja occidentalis L. essential oil, against malignant glioblastoma multiforme cells in vitro. Fitoterapia 134:172–181. https://doi.org/10.1016/j.fitote.2019.02.020

    Article  CAS  PubMed  Google Scholar 

  15. Lv L, Liu B (2017) Anti-tumor effects of bakuchiol on human gastric carcinoma cell lines are mediated through PI3K/AKT and MAPK signaling pathways. Mol Med Rep 16:8977–8982. https://doi.org/10.3892/mmr.2017.7696

    Article  CAS  PubMed  Google Scholar 

  16. Li J, Wang SX (2016) Synergistic enhancement of the antitumor activity of 5-fluorouracil by bornyl acetate in SGC-7901 human gastric cancer cells and the determination of the underlying mechanism of action. J BUON 21:108–117

    PubMed  Google Scholar 

  17. Girola N, Figueiredo CR, Farias CF et al (2015) Camphene isolated from essential oil of Piper cernuum (Piperaceae) induces intrinsic apoptosis in melanoma cells and displays antitumor activity in vivo. Biochem Biophys Res Commun 467:928–934. https://doi.org/10.1016/j.bbrc.2015.10.041

    Article  CAS  PubMed  Google Scholar 

  18. Günes-Bayir A, Kiziltan HS, Kocyigit A et al (2017) Effects of natural phenolic compound carvacrol on the human gastric adenocarcinoma (AGS) cells in vitro. Anticancer Drugs 28:522–530. https://doi.org/10.1097/CAD.0000000000000491

    Article  CAS  PubMed  Google Scholar 

  19. Baranauskaite J, Kubiliene A, Marksa M et al (2017) The influence of different oregano species on the antioxidant activity determined using HPLC postcolumn DPPH method and anticancer activity of carvacrol and rosmarinic acid. Biomed Res Int. https://doi.org/10.1155/2017/1681392

    Article  PubMed  PubMed Central  Google Scholar 

  20. Potočnjak I, Gobin I, Domitrović R (2018) Carvacrol induces cytotoxicity in human cervical cancer cells but causes cisplatin resistance: involvement of MEK–ERK activation. Phyther Res 32:1090–1097. https://doi.org/10.1002/ptr.6048

    Article  CAS  Google Scholar 

  21. Chaouki W, Leger DY, Liagre B et al (2009) Citral inhibits cell proliferation and induces apoptosis and cell cycle arrest in MCF-7 cells. Fundam Clin Pharmacol 23:549–556. https://doi.org/10.1111/j.1472-8206.2009.00738.x

    Article  CAS  PubMed  Google Scholar 

  22. Sheikh BY, Sarker MMR, Kamarudin MNA, Mohan G (2017) Antiproliferative and apoptosis inducing effects of citral via p53 and ROS-induced mitochondrial-mediated apoptosis in human colorectal HCT116 and HT29 cell lines. Biomed Pharmacother 96:834–846. https://doi.org/10.1016/j.biopha.2017.10.038

    Article  CAS  PubMed  Google Scholar 

  23. Bayala B, Bassole IHN, Maqdasy S et al (2018) Cymbopogon citratus and Cymbopogon giganteus essential oils have cytotoxic effects on tumor cell cultures. Identification of citral as a new putative anti-proliferative molecule. Biochimie 153:162–170. https://doi.org/10.1016/j.biochi.2018.02.013

    Article  CAS  PubMed  Google Scholar 

  24. Yu Y, Fu X, Ran Q et al (2017) Globularifolin exerts anticancer effects on glioma U87 cells through inhibition of Akt/mTOR and MEK/ERK signaling pathways in vitro and inhibits tumor growth in vivo. Biochimie 142:144–151. https://doi.org/10.1016/j.biochi.2017.09.005

    Article  CAS  PubMed  Google Scholar 

  25. Huang CH, Lu SH, Chang CC et al (2015) Hinokitiol, a tropolone derivative, inhibits mouse melanoma (B16–F10) cell migration and in vivo tumor formation. Eur J Pharmacol 746:148–157. https://doi.org/10.1016/j.ejphar.2014.11.011

    Article  CAS  PubMed  Google Scholar 

  26. Jayakumar T, Liu CH, Wu GY et al (2018) Hinokitiol inhibits migration of A549 lung cancer cells via suppression of MMPs and induction of antioxidant enzymes and apoptosis. Int J Mol Sci 19:1–13. https://doi.org/10.3390/ijms19040939

    Article  CAS  Google Scholar 

  27. Wei KC, Chen RF, Chen YF, Lin CH (2019) Hinokitiol suppresses growth of B16 melanoma by activating ERK/MKP3/proteosome pathway to downregulate survivin expression. Toxicol Appl Pharmacol 366:35–45. https://doi.org/10.1016/j.taap.2019.01.015

    Article  CAS  PubMed  Google Scholar 

  28. Yang B, Zhu R, Tian S et al (2017) Jatamanvaltrate P induces cell cycle arrest, apoptosis and autophagy in human breast cancer cells in vitro and in vivo. Biomed Pharmacother 89:1027–1036. https://doi.org/10.1016/j.biopha.2017.02.065

    Article  CAS  PubMed  Google Scholar 

  29. Mitropoulou G, Fitsiou E, Spyridopoulou K et al (2017) Citrus medica essential oil exhibits significant antimicrobial and antiproliferative activity. LWT - Food Sci Technol 84:344–352. https://doi.org/10.1016/j.lwt.2017.05.036

    Article  CAS  Google Scholar 

  30. Iwasaki K, Zheng YW, Murata S et al (2016) Anticancer effect of linalool via cancer-specific hydroxyl radical generation in human colon cancer. World J Gastroenterol 22:9765–9774. https://doi.org/10.3748/wjg.v22.i44.9765

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Han HD, Cho YJ, Cho SK et al (2016) Linalool-incorporated nanoparticles as a novel anticancer agent for epithelial ovarian carcinoma. Mol Cancer Ther 15:618–627. https://doi.org/10.1158/1535-7163.MCT-15-0733-T

    Article  CAS  PubMed  Google Scholar 

  32. Rodenak-Kladniew B, Islan GA, de Bravo MG et al (2017) Design, characterization and in vitro evaluation of linalool-loaded solid lipid nanoparticles as potent tool in cancer therapy. Colloids Surf B 154:123–132. https://doi.org/10.1016/j.colsurfb.2017.03.021

    Article  CAS  Google Scholar 

  33. Rodenak-Kladniew B, Castro A, Stärkel P et al (2018) Linalool induces cell cycle arrest and apoptosis in HepG2 cells through oxidative stress generation and modulation of Ras/MAPK and Akt/mTOR pathways. Life Sci 199:48–59. https://doi.org/10.1016/j.lfs.2018.03.006

    Article  CAS  PubMed  Google Scholar 

  34. Elgendy EM, Semeih MY (2019) Phyto – Monoterpene linalool as precursor to synthesis epoxides and hydroperoxides as anti carcinogenic agents via thermal and photo chemical oxidation reactions. Arab J Chem 12:966–973. https://doi.org/10.1016/j.arabjc.2018.09.008

    Article  CAS  Google Scholar 

  35. Martins BX, Arruda RF, Costa GA et al (2019) Myrtenal-induced V-ATPase inhibition - A toxicity mechanism behind tumor cell death and suppressed migration and invasion in melanoma. Biochim Biophys Acta 1863:1–12. https://doi.org/10.1016/j.bbagen.2018.09.006

    Article  CAS  Google Scholar 

  36. Seçme M, Eroğlu C, Dodurga Y, Bağci G (2016) Investigation of anticancer mechanism of oleuropein via cell cycle and apoptotic pathways in SH-SY5Y neuroblastoma cells. Gene 585:93–99. https://doi.org/10.1016/j.gene.2016.03.038

    Article  CAS  PubMed  Google Scholar 

  37. Andrade LN, Lima TC, Amaral RG et al (2015) Evaluation of the cytotoxicity of structurally correlated p-menthane derivatives. Molecules 20:13264–13280. https://doi.org/10.3390/molecules200713264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ma J, Li J, Wang KS et al (2016) Perillyl alcohol efficiently scavenges activity of cellular ROS and inhibits the translational expression of hypoxia-inducible factor-1α via mTOR/4E-BP1 signaling pathways. Int Immunopharmacol 39:1–9. https://doi.org/10.1016/j.intimp.2016.06.034

    Article  CAS  PubMed  Google Scholar 

  39. Oturanel CE, Kiran I et al (2017) Cytotoxic, antiproliferative and apoptotic effects of perillyl alcohol and its biotransformation metabolite on A549 and HepG2 cancer cell lines. Anticancer Agents Med Chem 17:1243–1250. https://doi.org/10.2174/1871520617666170103093923

    Article  CAS  PubMed  Google Scholar 

  40. De La Chapa JJ, Singha PK, Lee DR, Gonzales CB (2018) Thymol inhibits oral squamous cell carcinoma growth via mitochondria-mediated apoptosis. J Oral Pathol Med 47:674–682. https://doi.org/10.1111/jop.12735

    Article  CAS  Google Scholar 

  41. Günes-Bayir A, Kocyigit A, Güler EM, Kiziltan HS (2019) Effects of thymol, a natural phenolic compound, on human gastric adenocarcinoma cells in vitro. Altern Ther Health Med 25:12–21

    PubMed  Google Scholar 

  42. Gaonkar R, Shiralgi Y, Lakkappa DB, Hegde G (2018) Essential oil from Cymbopogon flexuosus as the potential inhibitor for HSP90. Toxicol Rep 5:489–496. https://doi.org/10.1016/j.toxrep.2018.03.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Jamali T, Kavoosi G, Safavi M, Ardestani SK (2018) In-vitro evaluation of apoptotic effect of OEO and thymol in 2D and 3D cell cultures and the study of their interaction mode with DNA. Sci Rep 8:1–19. https://doi.org/10.1038/s41598-018-34055-w

    Article  CAS  Google Scholar 

  44. Yang C, Chen H, Chen H et al (2017) Antioxidant and anticancer activities of essential oil from gannan navel orange peel. Molecules 22:1–10. https://doi.org/10.3390/molecules22081391

    Article  CAS  Google Scholar 

  45. Huang CH, Jayakumar T, Chang CC et al (2015) Hinokitiol exerts anticancer activity through downregulation of MMPs 9/2 and enhancement of catalase and SOD enzymes: In vivo augmentation of lung histoarchitecture. Molecules 20:17720–17734. https://doi.org/10.3390/molecules201017720

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Alves Batista F, Brena Cunha Fontele S, Beserra Santos LK et al (2019) Synthesis, characterization of α-terpineol-loaded PMMA nanoparticles as proposed of therapy for melanoma. Mater Today Commun. https://doi.org/10.1016/j.mtcomm.2019.100762

    Article  Google Scholar 

  47. Khan I, Bahuguna A, Kumar P et al (2018) In vitro and in vivo antitumor potential of carvacrol nanoemulsion against human lung adenocarcinoma A549 cells via mitochondrial mediated apoptosis. Sci Rep 8:712–714. https://doi.org/10.1038/s41598-017-18644-9

    Article  CAS  Google Scholar 

  48. Khan I, Bhardwaj M, Shukla S et al (2019) Carvacrol encapsulated nanocarrier/ nanoemulsion abrogates angiogenesis by downregulating COX-2, VEGF and CD31 in vitro and in vivo in a lung adenocarcinoma model. Colloids Surf B Biointerfaces 181:612–622. https://doi.org/10.1016/j.colsurfb.2019.06.016

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Antibiotics, Federal University of Pernambuco, Recife, Pernambuco, Brazil

    Bruno I. M. Silva, Erika A. Nascimento, Cleber J. Silva, Teresinha G. Silva & Jaciana S. Aguiar

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  1. Bruno I. M. Silva
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  2. Erika A. Nascimento
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  3. Cleber J. Silva
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All the authors contributed equally, in all stages, in the accomplishment of this work.

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Correspondence to Jaciana S. Aguiar.

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Silva, B.I.M., Nascimento, E.A., Silva, C.J. et al. Anticancer activity of monoterpenes: a systematic review. Mol Biol Rep 48, 5775–5785 (2021). https://doi.org/10.1007/s11033-021-06578-5

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