Chalcone-based NF-?B inhibition for post-carcinogen lung cancer chemoprevention Chalcone-based compounds have demonstrated chemopreventive activities against various types of malignancies, including post-carcinogen lung tumorigenesis, potentially via inhibiting the activation of NF-?B pathway. Their chemopreventive efficacy, however, has never been optimized, which may potentially delay the translational development and reduce their potential impact to cancer prevention. We have recently optimized chalcone-based compounds to improve their NF-?B inhibitory activities, leading to a set of lead candidates with distinct NF-?B inhibitory profiles and one lead compound demonstrating potent anticancer activity in vivo against lung cancer xenograft, which is hypothesized to have significantly more potent chemopreventive activity against post-carcinogen lung tumorigenesis. The goal of this research is to identify a safe and more efficacious chalcone-based chemopreventive agent against post-carcinogen lung cancer development, which may eventually help former smoker to prevent lung cancer development, and to establish the importance of NF-?B inhibition in chemoprevention. Experimentally, we will synthesize six chalcone lead compounds, including the one that has demonstrated post-carcinogen lung cancer chemopreventive activity. These chalcones will be evaluated in A/J mice for their post-carcinogen chemopreventive efficacy. The chemopreventive efficacies among these candidates in combination with their pre-determined NF-?B inhibitory activities will establish the relationship between chemoprevention and NF-?B inhibition, which will indirectly determine the relative importance of NF-?B inhibition in chalcone-induced chemoprevention. The relevance of NF-?B inhibition to chemoprevention will be further explored by analyzing NF-?B biomarkers, such as I?Ba and p-P65, in the lung adenoma tissues.

Public Health Relevance

Currently there is no effective agent that can help former smokers to avoid or delay lung cancer development. The goal of this study, based on the promising chemopreventive potential of chalcone against lung tumorigenesis in A/J mice and our systematic modification/optimization of chalcone-based compounds, is to identify the most chemopreventive compound(s) and to confirm the mechanism of action. Our long-term goal is to develop a safe and efficacious post-carcinogen chemopreventive agent that will prevent or delay lung cancer development among former smokers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Research Grants (R03)
Project #
5R03CA156301-02
Application #
8223221
Study Section
Special Emphasis Panel (ZCA1-SRLB-F (O1))
Program Officer
Perloff, Marjorie
Project Start
2011-02-07
Project End
2013-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
2
Fiscal Year
2012
Total Cost
$71,689
Indirect Cost
$21,689
Name
University of Minnesota Twin Cities
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
He, W; Wang, Q; Srinivasan, B et al. (2014) A JNK-mediated autophagy pathway that triggers c-IAP degradation and necroptosis for anticancer chemotherapy. Oncogene 33:3004-13
Srinivasan, Balasubramanian; Johnson, Thomas E; Xing, Chengguo (2011) Chalcone-based inhibitors against hypoxia-inducible factor 1--structure activity relationship studies. Bioorg Med Chem Lett 21:555-7