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

Abstract

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, χ2 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.

Lung cancer chemoprevention: current status and future directions

“…In addition, 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. Significant decreases in Akt and ERK phosphorylation were observed in bronchial dysplastic lesions following myoinositol treatment in heavy smokers [56]. All of these findings support the ongoing phase 2 multicenter study sponsored by the NCI Mayo Clinic Cancer Prevention Network (ClinicalTrials.gov identifier: NCT00783705).…”

Cancer Prevention: From 1727 to Milestones of the Past 100 Years

“…The mTOR inhibitor rapamycin was shown to be active in preclinical oral cancer prevention (320). The promising natural agent myoinositol regressed dysplastic bronchial lesions in heavy smokers via inhibition of active Akt (71).…”

“…Early reports of the related study of interventions with whole food products or food extracts as single compounds or in complex mixtures include a 1987 report on green tea polyphenols (66), a 1988 report on curcumin by the Conney group (67), a 1997 report on resveratrol (68), and recent reports on deguelin (69) and myoinositol (70), which has moved into clinical testing in the lung with promising results (71). An emerging area of great importance for interventions with natural compounds is nutrigenetics for identifying the populations most likely to benefit from specific compounds (72,73).…”

Natural-Agent Mechanisms and Early-Phase Clinical Development

“…Myo-inositol is a Natural-Agent Mechanisms and Early-Phase Clinical Developmentcomponent of the compound inositol hexaphosphate within its source foods, and inositol hexaphosphate is hydrolyzed by the enzyme phytase in the gastrointestinal tract to free myo-inositol. Myo-inositol has been shown to inhibit phospho-Akt [28] and to regulate PI3K expression signatures [29] in the lungs of smokers, suggesting the potential of this agent for cancer prevention.…”