Dimethylaminoparthenolide, A Water Soluble Parthenolide, Suppresses Lung Tumorigenesis Through Down-Regulating the STAT3 Signaling Pathway

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.