Chronic inflammation, mediated partly by tobacco smoke or environmental toxicants, plays a significant role in initiation and progression of lung cancer. Lung cancer progression is associated with increased activity of the transcription factor NF-?B, which is a major factor executing inflammatory response. Additionally, altered epigenetic program, as a consequence of elevated expression of histone deacetylases such as HDAC1 and histone methyl transferases such as EZH2, is observed in early stages of lung cancer. Therefore, an agent that can reduce the expression and/or activity of these proteins may serve as chemopreventive agent for lung cancer. During our search for agents with anti-NF-?B activity, we identified parthenolide as a novel agent that inhibits NF-?B and sensitizes cancer cells to chemotherapy. We developed a water-soluble analogue of this compound called LC-1, which is as potent as parthenolide but shows improved bioavailability and pharmacokinetics. LC-1 not only inhibited NF-?B but also reduced the levels of HDAC1 and its associated proteins CtBP1 and EZH2. HDAC1, CtBP1 and EZH2 constitute a transcription repression complex that mediates epigenetic silencing of tumor suppressor genes such as p14ARF and death-associated protein kinase-1 (DAPK1) in lung cancer. Additionally, LC-1 induced the expression of cell cycle kinase inhibitor p21 and the tumor suppressor/pro-apoptotic gene TAp73, which is expressed at low levels in lung cancer due to promoter methylation or deletion. Furthermore, LC-1 inhibited the growth of lung cancer cells in vitro and in xenograft models. LC-1 also reduced tobacco carcinogen-induced activation of NF-?B and cyclin D1 expression in non-transformed lung epithelial cells. Hypothesis: LC-1 serves as a potent chemopreventive agent for lung cancer by inhibiting two major carcinogenic stimuli- inflammations and epigenetic silencing of tumor suppressors.
Specific aims :
Aim I will test the chemopreventive activity of LC-1 in Urethane (an environmental toxicant)- induced lung cancer in FVB/N mice, which is critically dependent on inflammation and NF-?B activation in lung epithelial cells.
Aim 2 will test the effect of LC-1 on tobacco carcinogens 4-(methylnitrosamine)-1-3-Pyridyl-1- butanone- and benzo(a)pyrene-induced lung cancer in A/J mice, which shows extensive epigenetic silencing of tumor suppressor genes. By measuring the levels of activated NF-?B, and the expression levels of EZH2, HDAC1, CtBP1, ARF, and DAPK1 in lung tissues of untreated and LC-1 treated animals, we will investigate whether these proteins serve as biomarkers for lung cancer chemoprevention. As LC-1 will soon be tested in clinic as a treatment for leukemia, the proposed studies will enable speedy translation to clinic, particularly for current or ex-smokers.
| Shanmugam, Rajasubramaniam; Kusumanchi, Praveen; Appaiah, Hitesh et al. (2011) A water soluble parthenolide analog suppresses in vivo tumor growth of two tobacco-associated cancers, lung and bladder cancer, by targeting NF-?B and generating reactive oxygen species. Int J Cancer 128:2481-94 |
