Pluchino Lenora Ann, Liu Amethyst Kar-Yin, Wang Hwa-Chain Robert
Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, 2407 River Drive, Knoxville, TN 37996, USA; Graduate School of Genome Science and Technology, University of Tennessee, Knoxville, TN 37996, USA.
Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, 2407 River Drive, Knoxville, TN 37996, USA.
Free Radic Biol Med. 2015 Mar;80:12-26. doi: 10.1016/j.freeradbiomed.2014.12.015. Epub 2014 Dec 20.
Most breast cancers occur sporadically due to long-term exposure to low-dose carcinogens in the diet and the environment. Specifically, smoke, polluted air, and high-temperature cooked meats comprise multiple carcinogens, such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), benzo[α]pyrene (B[α]P), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). We sought to determine if these carcinogens act together to induce breast cell carcinogenesis, and if so, whether noncytotoxic dietary agents could intervene. We demonstrated that coexposure to physiologically achievable doses of NNK, B[α]P, and PhIP (NBP) holistically enhanced initiation and progression of breast cell carcinogenesis. Reactive oxygen species (ROS) and activation of the ERK pathway were transiently induced by NBP in each exposure, and cross talk between reinforced ROS elevation and ERK activation played an essential role in increased DNA oxidation and damage. After cumulative exposures to NBP, this cross talk contributed to enhanced initiation of cellular carcinogenesis and led to enhanced acquisition of cancer-associated properties. Using NBP-induced transient changes, such as ROS elevation and ERK pathway activation, and cancer-associated properties as targeted endpoints, we revealed, for the first time, that two less-studied dietary compounds, ergosterol and mimosine, at physiologically achievable noncytotoxic levels, were highly effective in intervention of NBP-induced cellular carcinogenesis. Combined ergosterol and mimosine were more effective than individual agents in blocking NBP-induced transient endpoints, including ROS-mediated DNA oxidation, which accounted for their preventive ability to suppress progression of NBP-induced cellular carcinogenesis. Thus, dietary components, such as mushrooms containing ergosterol and legumes containing mimosine, should be considered for affordable prevention of sporadic breast cancer associated with long-term exposure to environmental and dietary carcinogens.
大多数乳腺癌是由于长期接触饮食和环境中的低剂量致癌物而散发性发生的。具体而言，烟雾、污染空气和高温烹制的肉类含有多种致癌物，如4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK）、苯并[a]芘（B[a]P）和2-氨基-1-甲基-6-苯基咪唑[4,5-b]吡啶（PhIP）。我们试图确定这些致癌物是否共同作用诱导乳腺细胞癌变，如果是，无细胞毒性的膳食剂是否可以干预。我们证明，同时暴露于生理可达到剂量的NNK、B[a]P和PhIP（NBP）可整体增强乳腺细胞癌变的起始和进展。每次暴露时，NBP都会瞬时诱导活性氧（ROS）和ERK途径的激活，增强的ROS升高与ERK激活之间的相互作用在DNA氧化和损伤增加中起重要作用。在累积暴露于NBP后，这种相互作用有助于增强细胞癌变的起始，并导致与癌症相关特性的获得增加。以NBP诱导的瞬时变化，如ROS升高和ERK途径激活，以及与癌症相关的特性作为靶向终点，我们首次发现，两种研究较少的膳食化合物，麦角固醇和含羞草碱，在生理可达到的无细胞毒性水平下，对NBP诱导的细胞癌变具有高效的干预作用。麦角固醇和含羞草碱联合使用比单独使用更有效地阻断NBP诱导的瞬时终点，包括ROS介导的DNA氧化，这解释了它们抑制NBP诱导的细胞癌变进展的预防能力。因此，应考虑食用含有麦角固醇的蘑菇和含有含羞草碱的豆类等膳食成分，以经济实惠的方式预防与长期接触环境和膳食致癌物相关的散发性乳腺癌。
