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Dimethylaminoparthenolide, a water soluble parthenolide, suppresses lung tumorigenesis through down-regulating the
Jung M Song, Xuemin Qian, Pramod Upadhyayya
1Masonic Cancer Center, University of Minnesota, Mayo Mail Code 806, 420 Delaware Street SE, Minneapolis, MN 55455, USA. kassi012@umn.edu.
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.
Insights
Dimethylamino-parthenolide (DMAPT) shows promise in lung cancer prevention. This compound selectively inhibited lung cancer cell growth and reduced tumor multiplicity in mice, particularly larger tumors.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Lung cancer remains a leading cause of cancer mortality.
- Developing effective chemoprevention strategies is crucial for reducing lung cancer deaths.
- The STAT3 signaling pathway is frequently activated in lung cancers, promoting proliferation and survival.
Purpose of the Study:
- To investigate the potential of dimethylamino-parthenolide (DMAPT) as a lung cancer chemopreventive agent.
- To evaluate the efficacy of DMAPT in inhibiting lung tumorigenesis in vitro and in vivo.
- To elucidate the molecular mechanisms underlying DMAPT's anti-tumor effects.
Main Methods:
- In vitro studies using a lung tumorigenesis model to assess DMAPT's effects on cell growth and survival.
- In vivo studies involving a mouse model of tobacco smoke-induced lung tumors.
- Western immunoblotting to analyze protein levels (pSTAT3, Mcl-1) in lung tissues.
Main Results:
- DMAPT selectively inhibited premalignant and malignant lung cells in vitro with minimal effects on normal cells.
- DMAPT suppressed key proteins in the STAT3 signaling pathway, including pSTAT3 and Mcl-1.
- Intranasal administration of DMAPT significantly reduced overall lung tumor multiplicity by 39% in mice.
- DMAPT demonstrated a notable 62% reduction in larger lung tumors (> 2 mm).
Conclusions:
- DMAPT exhibits significant antiproliferative and apoptotic effects on lung cancer cells, partly via STAT3 pathway suppression.
- DMAPT is a promising candidate for lung cancer chemoprevention, particularly in high-risk individuals.
- The drug's efficacy against larger tumors suggests potential in preventing progression to adenocarcinoma.
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