Perillyl Alcohol

• How It Works

  A specific form of perillyl alcohol may be helpful in palliative care patients with recurrent gliomas. However, oral forms were not effective in several cancers and were accompanied by adverse side effects.

  Perillyl alcohol (POH) is a natural substance called a monoterpene, isolated from the essential oils of lavender, peppermint, spearmint, cherries, celery seeds, and several other plants. Laboratory evidence suggests that it interferes with the replication of dividing cells. POH has shown antitumor activity against a range of cancer types including pancreatic, lung, colon, and liver cancers in laboratory and animal studies, but these results have not yet translated into benefits in humans. Clinical trials of oral POH for various cancers including breast, prostate, and ovarian cancers did not find benefit and also noted adverse side effects, even after modifying dosing regimens to try to improve effectiveness and tolerability. However, an inhaled form of POH has shown preliminary evidence of safety and effectiveness in patients with recurrent gliomas. In addition, other purified forms are being studied as chemical modifiers of established drugs used to treat cancer in order to improve outcomes.

• Purported Uses
  • To prevent and treat cancer
    POH developed as a nasal spray has shown initial evidence of safety and effectiveness in palliative care patients with recurrent gliomas. A study of topical POH applied to sun-damaged skin did not suggest it could prevent skin cancers. Oral POH has yet to suggest benefit in humans and was also associated with adverse side effects.
• Side Effects
  • Oral POH: nausea, unpleasant taste, gastrointestinal distress, feeling full after eating a small amount of food, fatigue

    Toxicity can develop at high doses including nausea, fatigue, diarrhea, low blood potassium levels, inflamed oral mucous membranes, and loss of appetite. There have also been cases of vomiting, low white blood cell counts, and inflammation of the pancreas.

  • Intranasal POH: Initial studies have shown good tolerability and no adverse effects.
• Special Point

  Natural products such as tart cherry juice may contain POH. However, the POH that occurs in natural products are different from the highly purified forms that are being used for research and clinical trial purposes to determine safety and efficacy.

• Scientific Name

  p-metha,1,7-diene-6-ol, 4-isopropenyl-cyclohexenecarbinol

• Clinical Summary

  Perillyl alcohol (POH) is a naturally occurring monoterpene derived from the essential oils of various botanicals including lavender, peppermint, cherries, sage, and lemongrass. It has been used topically as a mosquito repellant and in toiletries, and may be touted as a constituent of natural products such as tart cherry juice.

  In vitro studies show that POH has antiangiogenesis ⁽⁹⁾ and anticancer ^{(11) (12) (16) (17)(18)} effects. Early animal studies also suggest tumor inhibition and regression ^{(4) (5) (19) (20) (21)}.

  In human studies, oral POH did not benefit patients with prostate ⁽¹⁰⁾, ovarian ⁽⁷⁾, or breast cancers ⁽¹⁴⁾. Another study attempting to achieve higher daily oral doses or better long-term tolerability in a variety of malignant tumors found no significant advantages with interrupted administration over continuous dosing schedules ⁽²²⁾. Topical POH also did not show chemopreventive effects in subjects with skin damage ⁽¹³⁾. These delivery methods were consequently abandoned due to either dose-limiting side effects and/or lack of efficacy ⁽²³⁾. More recent preliminary studies found intranasal POH delivery in patients with malignant gliomas to be well-tolerated and effective, with one study reporting tumor size regression ⁽¹⁵⁾, and another reporting increased overall survival and no side effects after long-term use ⁽²⁴⁾. Confirmatory studies are needed.

  POH is also in preclinical development as part of a novel drug to improve upon the effects of temozolomide (TMZ), which is used to treat a variety of cancers. TMZ conjugated to POH (TMZ-POH) increased anticancer activity in several breast cancer cell lines including those resistant to TMZ ⁽²⁵⁾. Animal models also suggest its potential for brain-targeted breast cancer metastases ⁽²⁵⁾, TMZ-resistant gliomas ⁽²⁶⁾, O6-methyl-guanine DNA methyltransferase (MGMT) melanomas ⁽²⁷⁾, and nasopharyngeal carcinomas ⁽²⁸⁾ versus TMZ alone or simply a mixture of TMZ and POH. Amino-modified POH derivatives are also being evaluated and have shown anticancer activity in human lung cancer, melanoma, and fibrosarcoma cells ⁽²⁹⁾.

  The POH that may occur in natural products are different from their scientifically studied counterparts, which are extracted from plants or developed synthetically into highly purified forms and are being used for research and clinical trial purposes to determine safety and efficacy.

• Purported Uses
  • Cancer prevention
  • Cancer treatment
• Mechanism of Action

  Perillyl alcohol metabolites perillic acid and dihydroperillic acid may prevent tumor growth through inhibition of p21-dependent signaling and apoptosis resulting from induction of the transforming growth factor beta-signaling pathway ^(1) (2). These metabolites also induce G1 cell cycle arrest, inhibit posttranslational modification of signal transduction proteins, and cause differential expression of cell cycle- and apoptosis-related genes ⁽³⁾. POH may also affect Ras signaling pathways ⁽³⁰⁾ and Na/K-ATPase inhibition ⁽³¹⁾. In addition, some POH glycosides, most particularly POH 4’-azido-D-glucoside (PG9), are identified as having improved antiproliferative activity and inhibition of S6 ribosomal protein phosphorylation ⁽³²⁾.

  Intranasal POH may be more successful than dose-limiting oral POH because it crosses the blood-brain barrier to enter the central nervous system, eliminating the need for systemic delivery and reducing unwanted systemic side effects ⁽³⁰⁾.

  In breast cancer cell lines and animal models, the more efficient DNA damage and cell death that occurs with the novel compound TMZ-POH versus TMZ alone was due to the increased biologic half-life acquired with POH linkage, providing more opportunity for placement of cytotoxic DNA lesions ⁽²⁵⁾. A combination of POH and lovastatin, which may also reduce glioma risk, impaired mevalonate- and Ras-Raf-MEK-ERK pathway regulation in glioblastoma cells ⁽³³⁾.

• Adverse Reactions

  Common (oral): nausea, unpleasant taste, gastrointestinal distress, early satiety, fatigue ^{(3) (10) (22)}.

  Rare (oral): vomiting ⁽²²⁾.

  At 1200 mg/m²/day: one instance of hypokalemia (low potassium levels) ⁽¹⁰⁾.
  At 1600 mg/m²/dose: gr 3 hypokalemia with course 2; acute pancreatitis in a patient with non-Hodgkin’s lymphoma during course 6 ⁽²²⁾.
  At 2000 mg/m²/dose: gr 2–3 hypokalemia over 2 courses ⁽²²⁾.
  At >2800 mg/m²/day: nausea, fatigue, diarrhea, hypokalemia, stomatitis, and anorexia ^(2) (8).
  At high doses on a tid schedule: gr 3 neutropenia in 2 heavily treated ovarian cancer patients ⁽³⁾.

• References

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

  2. 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.

  3. Ripple GH. Phase I clinical and pharmacokinetic study of perillyl alcohol administered four times a day. Clin Cancer Res 2000;6:390-6.

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

  5. Low-Baselli A, et al. Failure to demonstrate chemoprevention by the monoterpene perillyl alcohol during early rat hepatocarcinogenesis: a cautionary note. Carcinogenesis 2000;21:1869-77.

  6. Murren JR, et al. Phase I study of perillyl alcohol in patients with refractory malignancies. Cancer Biol Ther 2002;1:130-5.

  7. Bailey HH, et al. A phase II trial of daily perillyl alcohol in patients with advanced ovarian cancer: Eastern Cooperative Oncology Group study E2E96. Gynecol Oncol 2002;85:464-8.

  8. Azzoli C, et al. A phase I trial of perillyl alcohol in patients with advanced solid tumors. Cancer Chemother Pharmacol 2003 Jun;51(6):493-8.

  9. Loutrari H, Hatziapostolou M, Skouridou V, et al. Perillyl alcohol is an angiogenesis inhibitor. J Pharmacol Exp Ther. 2004 Jun 21

  10. Liu G, Oettel K, Bailey H, et al. Phase II trial of perillyl alcohol (NSC 641066) administered daily in patients with metastatic androgen independent prostate cancer. Invest New Drugs. 2003 Aug;21(3):367-72.

  11. Xu M, Floyd HS, Greth SM, et al. Perillyl alcohol-mediated inhibition of lung cancer cell line proliferation: potential mechanisms for its chemotherapeutic effects. Toxicol Appl Pharmacol. 2004 Mar 1;195(2):232-46.

  12. Fernandes J, da Fonseca CO, Teixeira A, Gattass CR. Perillyl alcohol induces apoptosis in human glioblastoma multiforme cells. Oncol Rep. 2005 May;13(5):943-7.

  13. Stratton SP, Alberts DS, Einspahr JG, et al. A phase 2a study of topical perillyl alcohol cream for chemoprevention of skin cancer. Cancer Prev Res (Phila). 2010 Feb;3(2):160-9.

  14. Bailey HH, Attia S, Love RR, et al. Phase II trial of daily oral perillyl alcohol (NSC 641066) in treatment-refractory metastatic breast cancer. Cancer Chemother Pharmacol. 2008 Jun;62(1):149-57.

  15. da Fonseca CO, Schwartsmann G, Fischer J, et al. Preliminary results from a phase I/II study of perillyl alcohol intranasal administration in adults with recurrent malignant gliomas. Surg Neurol. 2008 Sep;70(3):259-66; discussion 266-7.

  16. Koyama M, Sowa Y, Hitomi T, et al. Perillyl alcohol causes G1 arrest through p15(INK4b) and p21(WAF1/Cip1) induction. Oncol Rep. 2013 Feb;29(2):779-84.

  17. Sultana S, Nafees S, Khan A. Perillyl alcohol as a protective modulator against rat hepatocarcinogenesis via amelioration of oxidative damage and cell proliferation. Hum Exp Toxicol. 2013 Nov;32(11):1179-92.

  18. Bardon S, Picard K, Martel P. Monoterpenes inhibit cell growth, cell cycle progression, and cyclin D1 gene expression in human breast cancer cell lines. Nutr Cancer. 1998;32(1):1-7.

  19. Ziegler J. Raloxifene, retinoids, and lavender: “me too” tamoxifen alternatives under study. J Natl Cancer Inst. Aug 21 1996;88(16):1100-1102.

  20. Lantry LE, Zhang Z, Gao F, et al. Chemopreventive effect of perillyl alcohol on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone induced tumorigenesis in (C3H/HeJ X A/J)F1 mouse lung. J Cell Biochem Suppl. 1997;27:20-25.

  21. Burke YD, Ayoubi AS, Werner SR, et al. Effects of the isoprenoids perillyl alcohol and farnesol on apoptosis biomarkers in pancreatic cancer chemoprevention. Anticancer Res. Nov-Dec 2002;22(6a):3127-3134.

  22. Bailey HH, Wilding G, Tutsch KD, et al. A phase I trial of perillyl alcohol administered four times daily for 14 days out of 28 days. Cancer Chemother Pharmacol. Oct 2004;54(4):368-376.

  23. Bauml J, Chen L, Chen J, et al. Arthralgia among women taking aromatase inhibitors: is there a shared inflammatory mechanism with co-morbid fatigue and insomnia? Breast Cancer Res. 2015;17:89.

  24. da Fonseca CO, Simao M, Lins IR, et al. Efficacy of monoterpene perillyl alcohol upon survival rate of patients with recurrent glioblastoma. J Cancer Res Clin Oncol. Feb 2011;137(2):287-293.

  25. Chen TC, Cho HY, Wang W, et al. A novel temozolomide-perillyl alcohol conjugate exhibits superior activity against breast cancer cells in vitro and intracranial triple-negative tumor growth in vivo. Mol Cancer Ther. May 2014;13(5):1181-1193.

  26. Cho HY, Wang W, Jhaveri N, et al. NEO212, temozolomide conjugated to perillyl alcohol, is a novel drug for effective treatment of a broad range of temozolomide-resistant gliomas. Mol Cancer Ther. Aug 2014;13(8):2004-2017.

  27. Chen TC, Cho HY, Wang W, et al. A novel temozolomide analog, NEO212, with enhanced activity against MGMT-positive melanoma in vitro and in vivo. Cancer Lett. Mar 28 2015;358(2):144-151.

  28. Chen TC, Cho HY, Wang W, et al. Chemotherapeutic effect of a novel temozolomide analog on nasopharyngeal carcinoma in vitro and in vivo. J Biomed Sci. 2015;22(1):71.

  29. Hui Z, Zhang M, Cong L, et al. Synthesis and antiproliferative effects of amino-modified perillyl alcohol derivatives. Molecules. 2014;19(5):6671-6682.

  30. da Fonseca CO, Schwartsmann G, Fischer J, et al. Preliminary results from a phase I/II study of perillyl alcohol intranasal administration in adults with recurrent malignant gliomas. Surg Neurol. Sep 2008;70(3):259-266; discussion 266-257.

  31. Garcia DG, Amorim LM, de Castro Faria MV, et al. The anticancer drug perillyl alcohol is a Na/K-ATPase inhibitor. Mol Cell Biochem. Dec 2010;345(1-2):29-34.

  32. Nandurkar NS, Zhang J, Ye Q, et al. The identification of perillyl alcohol glycosides with improved antiproliferative activity. J Med Chem. Sep 11 2014;57(17):7478-7484.

  33. Afshordel S, Kern B, Clasohm J, et al. Lovastatin and perillyl alcohol inhibit glioma cell invasion, migration, and proliferation—impact of Ras-/Rho-prenylation. Pharmacol Res. Jan 2015;91:69-77.

  34. Da Fonseca CO, Teixeira RM, Silva JC, et al. Long-term outcome in patients with recurrent malignant glioma treated with Perillyl alcohol inhalation. Anticancer Res. Dec 2013;33(12):5625-5631.