title: Human breast tissue disposition and bioactivity of limonene in women with early-stage breast cancer.
abstract: Limonene is a bioactive food component found in citrus peel oil that has shown chemopreventive and chemotherapeutic activities in preclinical studies. We conducted an open-label pilot clinical study to determine the human breast tissue disposition of limonene and its associated bioactivity. We recruited 43 women with newly diagnosed operable breast cancer electing to undergo surgical excision to take 2 grams of limonene daily for two to six weeks before surgery. Blood and breast tissue were collected to determine drug/metabolite concentrations and limonene-induced changes in systemic and tissue biomarkers of breast cancer risk or carcinogenesis. Limonene was found to preferentially concentrate in the breast tissue, reaching high tissue concentration (mean = 41.3 μg/g tissue), whereas the major active circulating metabolite, perillic acid, did not concentrate in the breast tissue. Limonene intervention resulted in a 22% reduction in cyclin D1 expression (P = 0.002) in tumor tissue but minimal changes in tissue Ki67 and cleaved caspase-3 expression. No significant changes in serum leptin, adiponectin, TGF-β1, insulin-like growth factor binding protein-3 (IGFBP-3), and interleukin-6 (IL-6) levels were observed following limonene intervention. There was a small but statistically significant postintervention increase in insulin-like growth factor I (IGF-I) levels. We conclude that limonene distributed extensively to human breast tissue and reduced breast tumor cyclin D1 expression that may lead to cell-cycle arrest and reduced cell proliferation. Furthermore, placebo-controlled clinical trials and translational research are warranted to establish limonene's role for breast cancer prevention or treatment.
authors.affiliation: The University of Arizona Cancer Center, 1515 N Campbell Ave, Tucson, AZ 85724, USA. jam1@email.arizona.edu
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Miller
authors.forename: Julie E
authors.initials: JE
authors.lastname: Lang
authors.forename: Michele
authors.initials: M
authors.lastname: Ley
authors.forename: Ray
authors.initials: R
authors.lastname: Nagle
authors.forename: Chiu-Hsieh
authors.initials: CH
authors.lastname: Hsu
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Thompson
authors.forename: Catherine
authors.initials: C
authors.lastname: Cordova
authors.forename: Amy
authors.initials: A
authors.lastname: Waer
authors.forename: H-H Sherry
authors.initials: HH
authors.lastname: Chow
mesh_terms: D016588:Anticarcinogenic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000032:analysis*; D001940:Breast / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D002957:Citrus / Q000737:chemistry; D019938:Cyclin D1 / Q000378:metabolism; D053138:Cyclohexenes / Q000032:analysis / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D000077222:Limonene; D008875:Middle Aged; D039821:Monoterpenes / Q000032:analysis; D009367:Neoplasm Staging; D010865:Pilot Projects; D011379:Prognosis; D013729:Terpenes / Q000493:pharmacokinetics / Q000494:pharmacology*; D014018:Tissue Distribution; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D016588:Anticarcinogenic Agents; D014408:Biomarkers, Tumor; D053138:Cyclohexenes; D018972:Insulin-Like Growth Factor Binding Protein 3; D015850:Interleukin-6; D039821:Monoterpenes; D013729:Terpenes; D053773:Transforming Growth Factor beta1; D019938:Cyclin D1; D007334:Insulin-Like Growth Factor I; C078706:perillic acid; D000077222:Limonene; D053148:Caspase 3
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