Title:Dimethylaminoparthenolide, A Water Soluble Parthenolide, Suppresses Lung Tumorigenesis Through Down-Regulating the STAT3 Signaling Pathway
Volume: 14
Issue: 1
Author(s): Jung M. Song, Xuemin Qian, Pramod Upadhyayya, Kwon H. Hong and Fekadu Kassie
Affiliation:
Keywords:
Apoptosis, chemoprevention, dimethylaminoparthenolide, intranasal administration, mouse lung tumorigenesis, 4-
(methylnitrosamino)-1-(3-pyridyl)-1-butanone.
Abstract: 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.
