Monoterpenes & Cancer Prevention

limonene

Essential oils, the highly concentrated volatile, aromatic essences of plants, are a mainstay of aromatherapy but are also used in flavoring, perfumes and even as solvents. Researchers now think that two components of orange oil and lavender oil are a good bet to prevent and treat cancer.

Most essential oils contain monoterpenes--compounds that contain 10 carbon molecules often arranged in a ring. Monoterpenes are formed in the mevalonic acid pathway in plants. This is the same pathway that makes cholesterol in animals and humans. Early on, cancer researchers realized that some aspects of cholesterol metabolism were involved in cancer growth. They then discovered that plant monoterpenes interfered with animal cholesterol synthesis, thereby reducing cholesterol levels and reducing tumor formation in animals.1

Limonene and Perillyl Alcohol
Two widely studied monoterpenes are being evaluated for their anticancer activity--limonene from orange peel (Citrus sinensis) and perillyl alcohol from lavender (Lavandula angustifolia), cherries and peppermint.
Because limonene and perillyl affect the pathway that produces cholesterol, they can inhibit cholesterol synthesis, thereby eliminating a minor contributor to cancer formation.2

Monoterpenes also increase the levels of liver enzymes involved in detoxifying carcinogens, an effect that decreases the possibility carcinogens will cause cellular damage.2 In addition, monoterpenes stimulate apoptosis, a cellular self-destruction mechanism triggered when a cell's DNA is badly damaged.3 This safety feature is generally activated before a cell becomes cancerous. Finally, monoterpenes inhibit protein isoprenylation. The cell uses this process to help a protein--in this case the ras protein involved in cell growth--find its proper location within the cell.4 If ras is not in the right place, it becomes overactive and can spur cancerous cell growth.

Laboratory animal studies demonstrate that these two monoterpenes inhibit the formation of chemically induced breast, colon, liver, skin and pancreatic tumors.5 For example, animals fed a diet containing 5 percent orange peel oil had a significantly reduced risk of developing mammary tumors when treated with the chemical tumor inducer DMBA.6 Similarly, animals fed a 5-percent limonene diet had less chance of mammary tumor growth. Researchers noticed that in this experiment rat tumors also regressed, suggesting limonene may treat existing cancer as well as prevent it.

New drugs typically undergo three phases of clinical tests, each more rigorous than the previous: Phase I trials establish a toxic human dose, phase II trials determine a therapeutic dose and how it is metabolized, and phase III trials determine drug effectiveness. Extensive animal studies are done before phase I trials begin.

Phase I trials have so far shown that limonene is well tolerated by cancer patients and has little toxicity.7 Phase II trials, to test how well limonene actually works to reduce cancer, are under way at several institutions including the National Cancer Institute (NCI) in Bethesda, Md.

In other research, perillyl alcohol, a related compound, was found to be five times as active as limonene in regressing tumors.7 A diet of 2.5 percent perillyl alcohol caused 75 percent of chemically induced rat mammary tumors to regress.8 Perillyl alcohol is now being tested in NCI-sponsored phase I clinical trials as a treatment for advanced breast, ovarian and prostatic cancers at the University of Wisconsin, Madison.9 Researchers speculate that perillyl alcohol may also be effective against pancreatic cancer, which is extremely difficult to treat.10

The amount of monoterpenes needed to prevent cancer in humans is not established. Toxicity studies are incomplete, but the high doses required for chemotherapy may cause kidney damage and gastrointestinal problems. Both orange and lavender essential oils are safe to ingest; in fact, orange oil is a common food additive used for flavoring.

Few drugs have been developed that effectively treat cancer, so NCI is constantly searching for potential drug candidates. Many of these candidates, like limonene and perillyl alcohol, are natural products from herbs. For now though, these two concentrated substances remain in the realm of the laboratory--the doses being used in clinical trials are intended for treating cancer and must be monitored by a physician.



References
1. Elson CE, Yu SG. The chemoprevention of cancer by mevalonate-derived constituents of fruits and vegetables. J Nutr 1994;124:607-14.
2. Gould MN. Cancer chemoprevention and therapy by monoterpenes. Environ Health Perspect 1997;105:S977-9.
3. Mills JJ, et al. Induction of apoptosis in liver tumors by the monoterpene perillyl alcohol. Cancer Res 1995; 55:979-83.
4. Hohl RJ. Monoterpenes as regulators of malignant cell proliferation. In: American Institute for Cancer Research. Dietary Phytochemicals in Cancer Prevention and Treatment. New York: Plenum Press;1996.
5. Elson CE. Suppression of mevalonate pathway activities by dietary isoprenoids: protective roles in cancer and cardiovascular disease. J Nutr 1995;125:1666S-72S.
6. [Anonymous]. Clinical Development Plan: l-Perillyl Alcohol, J Cellular Biochem 1996;26S:137-48.
7. Crowell PL, et al. Antitumor effects of limonene and perillyl alcohol against pancreatic and breast cancer. In: American Institute for Cancer Research. Dietary Phytochemicals in Cancer Prevention and Treatment. New York: Plenum Press;1996.
8. Vigushin DM, et al. Phase I and pharmacokinetic study of d-limonene in patients with advanced cancer. Cancer Research Campaign Phase I/II Clinical Trials Committee. Cancer Chemother & Pharmacol 1998;42:111-17.
9. Ziegler J. Raloxifen, retinoids and lavender: "me too" tamoxifen alternatives under study. J Natl Canc Inst 1996;88:1100-1.
10. Stark MJ, et al. Chemotherapy of pancreatic cancer with the monoterpene perillyl alcohol. Cancer Letters 1995; 96:15-21.