Since former smokers are at an elevated risk to develop lung cancer and about half of all new lung cancer incidences are among former smokers, there is an urgent need to develop safe and efficacious chemopreventive agents to help former smokers control this deadly disease. Our long-term goal is to develop a Complementary and Alternative Medicine (CAM) modality based on natural food and beverages that will help former smokers to prevent or delay lung cancer development. The results of our recent studies strongly support the notion that kava, a long-standing beverage in the South Pacific Islands, is promising to prevent post-carcinogen lung cancer development, potentially through suppressing NF-kB activation. Our preliminary data also suggest that kava's chemopreventive efficacy can be improved by enriching its chemopreventive constituents. Such optimization may also lead to improved safety. The objectives of this application, therefore, are to improve kava's post-carcinogen chemopreventive efficacy, to establish chemopreventive kava's safety, to identify the origin of potential hepatotoxicity associated with commercial kava, and to explore the mechanisms, such as NF-kB inhibition, that are responsible for kava-induced chemoprevention. Specifically, the following four Aims will be pursued:
Aim 1. Determine the post-carcinogen chemopreventive efficacy of kava fractions against lung adenoma formation and establish the efficacy of the most chemopreventive fraction to inhibit lung lesion progression to adenocarcinoma Aim 2. Identify the origin of hepatotoxicity associated with commercial kava Aim 3. Characterize major chemicals in the most chemopreventive kava preparation for QC/QA of the future chemopreventive kava product Aim 4. Determine the effects of the most chemopreventive kava preparation on key signaling pathways, including the NF-kB pathway Upon accomplishing these aims, we will have (a) identified a kava preparation more efficacious and safer than the existing commercial product, (b) established its efficacy to prevent lung cancer progression to adenocarcinomas, (c) ascribed the origin of hepatoxicity associated with commercial kava to the non-polar fraction;(d) characterized active/signature chemicals for better QC/QA of the future kava product;and (e) provided mechanistic insights concerning key signaling pathways and possibly the molecular targets for kava-induced post-carcinogen lung cancer chemoprevention.
Lung cancer is the leading cause of death among all malignancies. Former smokers are at a high risk to develop lung cancer. This research focuses on identifying a kava-based safe CAM modality that can prevent NNK/B[a]P-induced lung tumorigenesis in A/J mice with post-carcinogen regimen, the outcome of which is expected to set the foundation for developing a chemopreventive CAM modality that will help former smokers to prevent/delay lung cancer. Project Narrative Lung cancer is the leading cause of death among all malignancies. Former smokers are at a high risk to develop lung cancer. This research focuses on identifying a kava-based safe CAM modality that can prevent NNK/B[a]P-induced lung tumorigenesis in A/J mice with post-carcinogen regimen, the outcome of which is expected to set the foundation for developing a chemopreventive CAM modality that will help former smokers to prevent/delay lung cancer.
|Xu, Jennings; Xu, Xiuling; Shi, Shaoqing et al. (2016) Autophagy-Mediated Degradation of IAPs and c-FLIP(L) Potentiates Apoptosis Induced by Combination of TRAIL and Chal-24. J Cell Biochem 117:1136-44|
|Tang, Su-Ni; Zhang, Jinhui; Jiang, Peixin et al. (2016) Gene expression signatures associated with suppression of TRAMP prostate carcinogenesis by a kavalactone-rich Kava fraction. Mol Carcinog 55:2291-2303|
|Shi, Shaoqing; Wang, Qiong; Xu, Jennings et al. (2015) Synergistic anticancer effect of cisplatin and Chal-24 combination through IAP and c-FLIPL degradation, Ripoptosome formation and autophagy-mediated apoptosis. Oncotarget 6:1640-51|
|Martin, Amanda C; Johnston, Ed; Xing, Chengguo et al. (2014) Measuring the chemical and cytotoxic variability of commercially available kava (Piper methysticum G. Forster). PLoS One 9:e111572|
|Narayanapillai, Sreekanth C; Leitzman, Pablo; O'Sullivan, M Gerard et al. (2014) Flavokawains a and B in kava, not dihydromethysticin, potentiate acetaminophen-induced hepatotoxicity in C57BL/6 mice. Chem Res Toxicol 27:1871-6|
|Narayanapillai, Sreekanth C; Balbo, Silvia; Leitzman, Pablo et al. (2014) Dihydromethysticin from kava blocks tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis and differentially reduces DNA damage in A/J mice. Carcinogenesis 35:2365-72|
|Leitzman, Pablo; Narayanapillai, Sreekanth C; Balbo, Silvia et al. (2014) Kava blocks 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis in association with reducing O6-methylguanine DNA adduct in A/J mice. Cancer Prev Res (Phila) 7:86-96|
|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|
|Johnson, Thomas E; Hermanson, David; Wang, Lei et al. (2011) Lung tumorigenesis suppressing effects of a commercial kava extract and its selected compounds in A/J mice. Am J Chin Med 39:727-42|
|Shaik, Ahmad Ali; Hermanson, David Lee; Xing, Chengguo (2009) Identification of methysticin as a potent and non-toxic NF-kappaB inhibitor from kava, potentially responsible for kava's chemopreventive activity. Bioorg Med Chem Lett 19:5732-6|