D-limonene

• How It Works

  D-limonene has not been shown to treat or prevent cancer.

  D-limonene is derived from the peels of citrus fruits. It showed anti-inflammatory, wound healing and anticancer effects in laboratory studies. D-limonene was shown to alter the signaling pathways within cancer cells in a way that stops cancer cells from multiplying and causes their death (this is called “apoptosis”). In animal models, D-limonene slowed the growth of pancreatic, stomach, colon, skin, and liver cancers. It also slowed formation of tumors and their progression in animals exposed to cancer-causing substances. However, these anticancer effects have not been shown in humans.

• Purported Uses
  • To prevent and treat cancer
    Although test tube and animal studies show that D-limonene has anti-cancer activity, this effect was not found in early clinical trials.
  • To treat heartburn and gastroesophageal reflux
    There is limited evidence to support this use. More studies are needed.
• Side Effects
  • Nausea
  • Vomiting
  • Diarrhea
  • Allergic skin rash
• Scientific Name

  p-mentha-1,8-diene

• Clinical Summary

  Derived from the peels of citrus fruits, D-limonene is a terpene used to prevent and treat cancer and is also promoted as a treatment for gastroesophageal reflux.

  In vitro and animal studies suggest that D-limonene has anti-inflammatory ^(13) (20), bactericidal ⁽¹⁹⁾, wound healing ⁽²¹⁾ and anticancer effects ^{(14) (16) (17) (18)}. It was also shown to enhance the activity of docetaxel against prostate cancer cells ⁽¹⁵⁾. An epidemiological study reported an inverse relationship between citrus peel consumption and squamous cell carcinoma ⁽⁴⁾, but an early clinical trial in breast cancer patients failed to support the observations ^(5) (6). Further research is necessary to determine if D-limonene has a role in the prevention or treatment of cancer.

• Purported Uses
  • Cancer prevention
  • Cancer treatment
  • Heartburn and GERD (gastroesophageal reflux)
• Mechanism of Action

  D-Limonene and its metabolites, perillic acid, dihydroperillic acid, uroterpenol, and limonene1,2-diol, may inhibit tumor growth via inhibition of p21-dependent signaling and apoptosis resulting from induction of the transforming growth factor beta-signaling pathway ^(9) (10). D-Limonene metabolites also cause G1 cell cycle arrest, inhibit post-translational modification of signal transduction proteins, and cause differential expression of cell cycle- and apoptosis-related genes ⁽⁶⁾.

  D-limonene induces apoptosis via the mitochondrial death pathway and suppression of the PI3K/Akt pathway in human colon cancer cells ⁽¹⁶⁾. Animal studies show activity of D-limonene against pancreatic, stomach, colon, skin, and liver cancers ^(5) (17). Data also indicate that D-limonene slows the promotion/progression stage of carcinogen-induced tumors in rats ^(11) (12). The chemopreventive activity of D-limonene may be via inhibition of inflammation, oxidative stress and Ras-signaling as well as the induction of pro-apoptotic state in a mouse model of skin tumorigenesis ⁽¹⁸⁾.

  D-limonene and its metabolite perillyl alcohol were shown to affect wound healing by decreasing systemic cytokine production, and by inhibiting endothelial P-selectin expression and neo-vascularization ⁽²¹⁾.

• Adverse Reactions
  • Nausea, vomiting, diarrhea ⁽³⁾
  • Case Reports: Contact Dermatitis ^(7) (22) and asthma ⁽⁸⁾ have been reported.
• References

  1. Crowell PL, et al. Human metabolism of the experimental cancer therapeutic agent d-limonene. Cancer Chemother Pharmacol 1994;35:31-7.

  2. Hardcastle IR, et al. Inhibition of protein prenylation by metabolites of limonene. Biochem Pharmacol 1999;57:801-9.

  3. Vigushin DM, et al. Phase I and pharmacokinetic study of d-limonene in patients with advanced cancer. Cancer Chemother Pharmacol 1998;42:111-7.

  4. Hakim IA, Harris RB, Ritenbaugh C. Citrus peel use is associated with reduced risk of squamous cell carcinoma of the skin. Nutr Cancer. 2000;37(2):161-168.

  5. Belanger JT. Perillyl alcohol: applications in oncology. Altern Med Rev 1998;3:448-57.

  6. Reddy BS, et al. Chemoprevention of colon carcinogenesis by dietary perillyl alcohol. Cancer Res 1997;57:420-5.

  7. Topham EJ, Wakelin SH. D-Limonene contact dermatitis from hand cleansers. Contact Dermatitis. 2003 Aug;49(2):108-9.

  8. Guarneri F, Barbuzza O, Vaccaro M, et al. Allergic contact dermatitis and asthma caused by limonene in a labourer handling citrus fruits. Contact Dermatitis. May 2008;58(5):315-316.

  9. Hudes GR, et al. Phase I pharmacokinetic trial of perillyl alcohol (NSC 641066) in patients with refractory solid malignancies. Clin Cancer Res 2000;6:3071-80.

  10. Kaji I, et al. Inhibition by d-limonene of experimental hepatocarcinogenesis in Sprague-Dawley rats does not involve p21(ras) plasma membrane association. Int J Cancer 2001;93:441-4.

  11. Asamoto M, et al. Mammary carcinomas induced in human c-Ha-ras proto-oncogene transgenic rats are estrogen-independent, but responsive to d-limonene treatment. Jpn J Cancer Res 2002;93:32-5.

  12. Uedo N, et al. Inhibition by d-limonene of gastric carcinogenesis induced by N-methyl-N’-nitro-N-nitrosoguanidine in Wistar rats. Cancer Lett 1999;137:131-6.

  13. Yoon WJ, Lee NH, Hyun CG. Limonene suppresses lipopolysaccharide-induced production of nitric oxide, prostaglandin E2, and pro-inflammatory cytokines in RAW 264.7 macrophages. J Oleo Sci. 2010;59(8):415-21.

  14. Manuele MG, Barreiro Arcos ML, Davicino R, et al. Limonene exerts antiproliferative effects and increases nitric oxide levels on a lymphoma cell line by dual mechanism of the ERK pathway: relationship with oxidative stress. Cancer Invest. 2010 Feb;28(2):135-45.

  15. Rabi T, Bishayee A. d -Limonene sensitizes docetaxel-induced cytotoxicity in human prostate cancer cells: Generation of reactive oxygen species and induction of apoptosis. J Carcinog. 2009;8:9.

  16. Jia SS, Xi GP, Zhang M, et al. Induction of apoptosis by D-limonene is mediated by inactivation of Akt in LS174T human colon cancer cells.Oncol Rep. 2013 Jan;29(1):349-54.

  17. Chidambara Murthy KN, Jayaprakasha GK, Patil BS. D-limonene rich volatile oil from blood oranges inhibits angiogenesis, metastasis and cell death in human colon cancer cells.Life Sci. 2012 Oct 5;91(11-12):429-39.

  18. Chaudhary SC, Siddiqui MS, Athar M, Alam MS. D-Limonene modulates inflammation, oxidative stress and Ras-ERK pathway to inhibit murine skin tumorigenesis.Hum Exp Toxicol. 2012 Aug;31(8):798-811.

  19. Espina L, Gelaw TK, de Lamo-Castellví S, Pagán R, García-Gonzalo D. Mechanism of bacterial inactivation by (+)-limonene and its potential use in food preservation combined processes. PLoS One. 2013;8(2):e56769.

  20. d’Alessio PA, Ostan R, Bisson JF, Schulzke JD, Ursini MV, Béné MC. Oral administration of d-limonene controls inflammation in rat colitis and displays anti-inflammatory properties as diet supplementation in humans. Life Sci. 2013 Jul 10;92(24-26):1151-6.

  21. d’Alessio PA, Mirshahi M, Bisson JF, Bene MC. Skin repair properties of d-Limonene and perillyl alcohol in murine models. Antiinflamm Antiallergy Agents Med Chem. 2014 Mar;13(1):29-35.

  22. Pesonen M, Suomela S, Kuuliala O, Henriks-Eckerman ML, Aalto-Korte K. Occupational contact dermatitis caused by D-limonene. Contact Dermatitis. 2014 Nov;71(5):273-9.