Human breast tissue disposition and bioactivity of limonene in women with early-stage breast cancer.
Human breast tissue disposition and bioactivity of limonene in women with early-stage breast cancer.
复制标题
DOI：
10.1158/1940-6207.capr-12-0452
复制
发表时间：
2013-06
期刊：
影响因子：
--
通讯作者：
Chow HH
中科院分区：
文献类型：
--
作者：
Miller JA;Lang JE;Ley M;Nagle R;Hsu CH;Thompson PA;Cordova C;Waer A;Chow HH
柠檬烯是一种在柑橘皮油中发现的生物活性食品成分，在临床前研究中已显示出化学预防和化学治疗活性。我们进行了一项开放标记的先导性临床研究，以确定柠檬烯在人体乳腺组织中的分布及其相关生物活性。我们招募了43名新诊断为可手术乳腺癌的妇女，她们选择在手术前接受手术切除，每天服用2克柠檬烯，持续2-6周。采集血液和乳腺组织，以确定药物/代谢物浓度和柠檬烯诱导的乳腺癌风险或致癌风险的系统和组织生物标志物的变化。柠檬烯优先集中在乳房组织中，达到较高的组织浓度(平均为41.3μg/g组织)，而循环中主要的活性代谢物紫苏酸不集中在乳房组织中。柠檬烯干预可使肿瘤组织中细胞周期蛋白D1的表达降低22%(P=0.002)，而对Ki67和裂解半胱氨酸天冬氨酸蛋白酶3的表达无明显影响。柠檬烯干预后血清瘦素、脂联素、转化生长因子-β-1、胰岛素样生长因子结合蛋白-3和IL-6水平无明显变化。干预后IGF-1水平有少量但有统计学意义的增加。结论：柠檬烯广泛分布于人乳腺组织，降低乳腺肿瘤细胞周期蛋白D1的表达，可能导致细胞周期停滞，抑制细胞增殖。进一步的安慰剂对照临床试验和转化性研究是有必要的，以确定柠檬烯在乳腺癌预防或治疗中的作用。
Limonene is a bioactive food component found in citrus peel oil that has demonstrated 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 forty-three women with newly diagnosed operable breast cancer electing to undergo surgical excision to take 2 grams of limonene daily for 2 – 6 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) while 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, IGFBP-3 and IL-6 levels were observed following limonene intervention. There was a small but statistically significant post-intervention increase in IGF-1 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. Further placebo-controlled clinical trials and translational research are warranted to establish limonene’s role for breast cancer prevention or treatment.