Authors : Akshita B.; Lubna Fathima; Gibbson Derick D.; Sindhu R.; Prabu D.; Rajmohan M.; Dinesh Damodhar

Volume/Issue : Volume 10 - 2025, Issue 11 - November

Google Scholar : https://tinyurl.com/4rmcev38

Scribd : https://tinyurl.com/27s53du7

DOI : https://doi.org/10.38124/ijisrt/25nov221

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Abstract : Background: Limonene, a monocyclic monoterpene abundantly found in Eucalyptus oil and citrus fruits, has gained increasing attention for its potential anticancer properties. Limonene may be safe and well-tolerated while suppressing tumor development, inducing apoptosis, and modulating many molecular pathways, according to preclinical and clinical studies.It is a promising candidate for cancer prevention and treatment due to its natural origin, bioavailability, and selective accumulation in lipid-rich tissues.With an emphasis on its modes of action, safety profile, and therapeutic potential across a range of cancer models, the current review attempts to assess the concentration, dosage, and anticancer effects of limonene extract from eucalyptus oil.  Materials and Methods: A thorough search was conducted using databases such as PubMed, Scopus, and Google Scholar to gather pertinent studies on limonene's anticancer effects. In vitro, in vivo, and clinical investigations were analyzed to determine its bioactivity, tissue distribution, effective dosage ranges, and molecular interactions. The collected data was examined and presented to provide a full understanding of the role of limonene in cancer treatment.  Results: Limonene has shown considerable anticancer action in a dose-dependent manner by inducing apoptosis, autophagy, and arresting the G2/M cell cycle. It affects key pathways like caspase activation, Ras signaling, p53 regulation, and oxidative stress mitigation. Clinical investigations have shown its safety, with little gastrointestinal symptoms noted at therapeutic levels. Combination therapy with drugs like curcumin and andrographolide improves efficacy, whereas derivatives like perillyl alcohol improve potency and selectivity.  Conclusion: Limonene is a safe, bioactive, multifunctional chemical with powerful anticancer properties. However, variations in concentration, dose, and formulation indicate the need for more standardized clinical trials to optimize delivery methods and establish their therapeutic significance in cancer treatment.

Keywords : Limonene, Eucalyptus oil, Anticancer, Apoptosis, Autophagy, Bioavailability.

References :

1. Zheng R, Wang S, Zhang S, Zeng H, Chen R, Sun K, Li L, Bray F, Wei W. Global, regional, and national lifetime probabilities of developing cancer in 2020. Sci Bull (Beijing). 2023 Nov 15;68(21):2620-2628. doi: 10.1016/j.scib.2023.09.041. Epub 2023 Sep 29. PMID: 37821267; PMCID: PMC10640926.
2. Mattiuzzi C, Lippi G. Current Cancer Epidemiology. J Epidemiol Glob Health. 2019 Dec;9(4):217-222. doi: 10.2991/jegh.k.191008.001. PMID: 31854162; PMCID: PMC7310786.
3. Yu X, Lin H, Wang Y, Lv W, Zhang S, Qian Y, Deng X, Feng N, Yu H, Qian B. d-limonene exhibits antitumor activity by inducing autophagy and apoptosis in lung cancer. Onco Targets Ther. 2018 Apr 4; 11:1833-1847. doi: 10.2147/OTT.S155716. PMID: 29670359; PMCID: PMC5894671.
4. Čmiková N, Galovičová L, Schwarzová M, Vukic MD, Vukovic NL, Kowalczewski PŁ, Bakay L, Kluz MI, Puchalski C, Kačániová M. Chemical Composition and Biological Activities of Eucalyptus globulus Essential Oil. Plants (Basel). 2023 Feb 28;12(5):1076. doi: 10.3390/plants12051076. PMID: 36903935; PMCID: PMC10004840
5. Alghamdi AAA. D-Limonene Exhibits Antiproliferative Activity Against Human Colorectal Adenocarcinoma (Caco-2) Cells via Regulation of Inflammatory and Apoptotic Pathways. Curr Issues Mol Biol. 2025 May 18;47(5):370. doi: 10.3390/cimb47050370. PMCID: PMC12109675.
6. Hard GC, Whysner J. Risk assessment of d-limonene: an example of male rat-specific renal tumorigens. Crit Rev Toxicol. 1994;24(3):231-54. doi: 10.3109/10408449409021607. PMID: 7945892.
7. Vigushin DM, Poon GK, Boddy A, English J, Halbert GW, Pagonis C, Jarman M, Coombes RC, Cancer Research Campaign Phase I/II Clinical Trials Committee. Phase I and pharmacokinetic study of D-limonene in patients with advanced cancer. Cancer chemotherapy and pharmacology. 1998 Jun;42(2):111-7.
8. Ye Z, Liang Z, Mi Q, Guo Y. Limonene terpenoid obstructs human bladder cancer cell (T24 cell line) growth by inducing cellular apoptosis, caspase activation, G2/M phase cell cycle arrest and stops cancer metastasis. J. BUON. 2020 Jan 1;25(1):280-5.
9. Miller JA, Thompson PA, Hakim IA, Lopez AM, Thomson CA, Chew W, Hsu CH, Chow HS. Safety and feasibility of topical application of limonene as a massage oil to the breast. Journal of cancer therapy. 2012 Oct;3(5A):10-4236.
10. Hanif H, Elikaei A, Vazini H, Mohammadi A. Anticancer and Antibacterial Effect of Eucalyptus Camaldulensis, in Vitro. Medical Laboratory Journal. 2021 Jan 10;15(1):26-32.
11. Crowell PL, Gould MN. Chemoprevention and therapy of cancer by d-limonene. Critical Reviews™ in Oncogenesis. 1994;5(1).
12. Lu XG, Zhan LB, Feng BA, Qu MY, Yu LH, Xie JH. Inhibition of growth and metastasis of human gastric cancer implanted in nude mice by d-limonene. World Journal of Gastroenterology: WJG. 2004 Jul 15;10(14):2140.
13. Chander SK, Lansdown AG, Luqmani YA, Gomm JJ, Coope RC, Gould N, Coombes RC. Effectiveness of combined limonene and 4-hydroxyandrostenedione in the treatment of NMU-induced rat mammary tumours. British journal of cancer. 1994 May;69(5):879-82.
14. Haag JD, Lindstrom MJ, Gould MN. Limonene-induced regression of mammary carcinomas. Cancer research. 1992 Jul 15;52(14):4021-6.
15. Asamoto M, Ota T, Toriyama‐Baba H, Hokaiwado N, Naito A, Tsuda H. Mammary carcinomas induced in human c‐Ha‐ras proto‐oncogene transgenic rats are estrogen‐independent, but responsive to d‐limonene treatment. Japanese journal of cancer research. 2002 Jan;93(1):32-5.
16. Vukmirovic D, Vo NT, Seymour C, Rollo D, Mothersill C. Influence of common dietary supplements (curcumin, andrographolide, and d-limonene) on the radiobiological responses of p53-competent colonic cancer epithelial cells. International Journal of Radiation Biology. 2021 Mar 4;97(3):341-7.
17. Da Silva CE, Gosmann G, de Andrade SF. Limonene and perillyl alcohol derivatives: Synthesis and anticancer activity. Mini Reviews in Medicinal Chemistry. 2021 Aug 1;21(14):1813-29.
18. Vukmirovic D, Vo NT, Seymour C, Rollo D, Mothersill C. Influence of common dietary supplements (curcumin, andrographolide, and d-limonene) on the radiobiological responses of p53-competent colonic cancer epithelial cells. International Journal of Radiation Biology. 2021 Mar 4;97(3):341-7.
19. Sun J. D-Limonene: safety and clinical applications. Alternative medicine review. 2007 Sep 1;12(3):259.
20. Mukhtar YM, Adu-Frimpong M, Xu X, Yu J. Biochemical significance of limonene and its metabolites: future prospects for designing and developing highly potent anticancer drugs. Bioscience Reports. 2018 Nov 14;38(6): BSR20181253.
21. Lu XG, Zhan LB, Feng BA, Qu MY, Yu LH, Xie JH. Inhibition of growth and metastasis of human gastric cancer implanted in nude mice by d-limonene. World Journal of Gastroenterology: WJG. 2004 Jul 15;10(14):2140.