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The Chemopreventive Agent Myoinositol Inhibits Akt and Extracellular Signal-Regulated Kinase in Bronchial Lesions from Heavy Smokers

Authors' Affiliations: ¹ Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland and ² Departments of Respiratory Medicine, and Cancer Imaging, British Columbia Cancer Agency and the University of British Columbia, Vancouver, British Columbia, Canada

Requests for reprints: Phillip A. Dennis, National Cancer Institute/Navy Medical Oncology, Room 5101, Building 8, 8901 Wisconsin Avenue, Bethesda, MD 20889. Phone: 301-496-0929; Fax: 301-496-0047; E-mail: pdennis{at}nih.gov.

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, 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 G₁-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.

Key Words: Myoinositol • Akt • ERK • immunohistochemistry • bronchial dysplasia

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