Honokiol inhibits lung tumorigenesis through inhibition of mitochondrial function.
Honokiol inhibits lung tumorigenesis through inhibition of mitochondrial function.
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DOI：
10.1158/1940-6207.capr-14-0091
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发表时间：
2014-11
期刊：
影响因子：
--
通讯作者：
You M
中科院分区：
文献类型：
--
作者：
Pan J;Zhang Q;Liu Q;Komas SM;Kalyanaraman B;Lubet RA;Wang Y;You M
厚朴酚是木兰树皮中发现的一种重要的生物活性物质。它是一种非脂肪形成性PPARγ激动剂，能够在体外和异种移植模型中抑制多种肿瘤类型的生长。然而，为了充分认识和诺酮的潜在化学预防活性，需要较少的人工模型系统。为此，本研究在鳞状细胞肺癌（SCC）的起始模型中检查了和诺明的化学预防功效。该模型系统使用局部应用的致癌物N-亚硝基-三氯乙基脲（NTCU），在24-26周内可靠地触发SCC的发展。施用和厚朴酚显著降低了表现出异常肺SCC组织学的支气管的百分比，从对照组的24.4%支气管降低到和厚朴酚治疗组的11.0%支气管（p= 0.01），同时保护了正常支气管组织学（存在于对照组的20.5%支气管和和厚朴酚治疗组的38.5%支气管（p= 0.004））。SCC部位P63染色证实了肺SCC表型。体外研究表明，和厚朴酚可抑制肺鳞癌细胞增殖，使细胞阻滞在G1/S细胞周期检查点，同时也导致细胞凋亡增加。我们的研究表明，干扰线粒体呼吸是一种新的机制，通过这种机制，和厚朴酚增加了线粒体中活性氧（ROS）的产生，引发细胞凋亡，并最终导致肺SCC的抑制。这种靶向线粒体的新机制表明和诺明是一种潜在的肺SCC化学预防剂。
Honokiol is an important bioactive compound found in the bark of Magnolia tree. It is a non-adipogenic PPARγ agonist, and capable of inhibiting the growth of a variety of tumor types both in vitro and in xenograft models. However, to fully appreciate the potential chemopreventive activity of honokiol, a less artificial model system is required. To that end, this study examined the chemopreventive efficacy of honokiol in an initiation model of squamous cell lung cancer (SCC). This model system uses the carcinogen N-nitroso-trischloroethylurea (NTCU) which is applied topically, reliably triggering the development of SCC within 24–26 weeks. Administration of honokiol significantly reduced the percentage of bronchial that exhibit abnormal lung SCC histology from 24.4% bronchial in control to 11.0% bronchial in honokiol treated group (p= 0.01) while protecting normal bronchial histology (present in 20.5% of bronchial in control group and 38.5% of bronchial in honokiol treated group (p= 0.004)). P63 staining at the SCC site confirmed the lung SCCs phenotype. In vitro studies revealed that honokiol inhibited lung SCC cells proliferation, arrested cells at the G1/S cell cycle checkpoint, while also leading to increased apoptosis. Our study showed that interfering with mitochondrial respiration is a novel mechanism by which honokiol increased generation of reactive oxygen species (ROS) in the mitochondria, triggered apoptosis, and finally leads to the inhibition of lung SCC. This novel mechanism of targeting mitochondrial suggests honokiol as a potential lung SCC chemopreventive agent.