Lung cancer is the most fatal
cancer and development of agents that suppress lung
tumorigenesis is a crucial strategy to reduce mortality related to this disease. In the present study, we showed, using an in vitro model of lung
tumorigenesis, that
dimethylamino-parthenolide (DMAPT), a water soluble
parthenolide analog, selectively inhibited the growth and survival of premalignant and malignant cells with minimal effects on parental immortalized cells. These effects were paralleled by suppression of pSTAT3, Mcl-1 and
cyclin D1 and PARP cleavage, suggesting that the antiproliferative and apoptotic effects of DMAPT could be mediated, at least in part, via suppression of the STAT3 signaling pathway. Moreover, in tobacco
smoke carcinogen-induced lung
tumor bioassay in mice, intranasal instillation of low doses of DMAPT significantly reduced the overall lung
tumor multiplicity by 39%. Interestingly, the
drug was specifically effective (62% reduction) against bigger lung
tumors (> 2 mm), which have a higher potential to develop into
lung adenocarcinoma. Western immunoblotting analyses of mouse lung tissues indicated significantly lower level of pSTAT3 and Mcl-1 in the
carcinogen plus DMAPT group relative to the group treated with the
carcinogen only. Given the evidence that STAT3 is activated in more than half of
lung cancers and it regulates genes involved in cell proliferation, survival and angiogenesis, DMAPT is a promising agent for
lung cancer chemoprevention in subjects who are at high risk of developing this devastating disease.