The Chemopreventive Agent Myoinositol Inhibits Akt and Extracellular Signal-Regulated Kinase in Bronchial Lesions from Heavy Smokers
The Chemopreventive Agent Myoinositol Inhibits Akt and Extracellular Signal-Regulated Kinase in Bronchial Lesions from Heavy Smokers
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DOI：
10.1158/1940-6207.capr-08-0209
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发表时间：
2009-04-01
影响因子：
3.3
通讯作者：
Dennis, Phillip A.
中科院分区：
文献类型：
--
作者：
Han, Wei;Gills, Joell J.;Dennis, Phillip A.
肌醇是葡萄糖的异构体，在癌症动物模型中具有化学预防活性。在最近的一项I期临床试验中，肌醇给药与重度吸烟者既存支气管发育不良病变的统计学显著性消退相关。为了阐明所涉及的潜在机制，在参加本临床试验的21名患者的206对支气管活检中评估了Akt和细胞外信号调节激酶（ERK）（两种控制细胞增殖和生存的激酶）的激活。在肌醇治疗前，27%的增生/化生病变和58%的不典型增生病变中检测到Akt活化的强阳性染色（P = 0.05，卡方检验）。ERK的激活也有增加的趋势（增生/化生区域为28%，发育不良病变为42%）。肌醇治疗后，Akt和ERK磷酸化水平在异型增生中显著降低（分别为P < 0.01和0.05），但在增生/化生中无显著降低（P > 0.05）。在体外，肌醇降低内源性和烟草致癌物诱导的永生化人支气管上皮细胞中Akt和ERK的激活，从而降低细胞增殖并诱导G（1）-S细胞周期停滞。这些结果表明，吸烟者癌前支气管病变的表型进展与Akt和ERK的活化增加相关，这些激酶是肌醇的靶点。此外，他们认为肌醇可能通过抑制活性Akt和ERK而引起支气管发育不良病变的消退。
Myoinositol is an isomer of glucose that has chemopreventive activity in animal models of cancer. In a recent phase I clinical trial, myoinositol administration correlated with a statistically significant regression of preexisting bronchial dysplastic lesions in heavy smokers. To shed light on the potential mechanisms involved, activation of Akt and extracellular signal-regulated kinase (ERK), two kinases that control cellular proliferation and survival, was assessed in 206 paired bronchial biopsies from 21 patients who participated in this clinical trial. Before myoinositol treatment, strongly positive staining for activation of Akt was detected in 27% of hyperplastic/metaplastic lesions and 58% of dysplastic lesions (P = 0.05, chi(2) test). There was also a trend toward increased activation of ERK (28% in regions of hyperplasia/metaplasia to 42% of dysplastic lesions). Following myoinositol treatment, significant decreases in Akt and ERK phosphorylation were observed in dysplastic (P < 0.01 and 0.05, respectively) but not hyperplastic/metaplastic lesions (P > 0.05). In vitro, myoinositol decreased endogenous and tobacco carcinogen-induced activation of Akt and ERK in immortalized human bronchial epithelial cells, which decreased cell proliferation and induced a G(1)-S cell cycle arrest. These results show that the phenotypic progression of premalignant bronchial lesions from smokers correlates with increased activation of Akt and ERK and that these kinases are targets of myoinositol. Moreover, they suggest that myoinositol might cause regression of bronchial dysplastic lesions through inhibition of active Akt and ERK.