Bladder cancer represents a major public health burden. The cost per bladder cancer patient from diagnosis to death is the highest among all cancers ($96,000 to $187, 000 per patient in the US). Our long-term goal is to develop new chemopreventive agents to reduce the burden of bladder cancer. Because exposure to carcinogens is the major risk factor for bladder cancer and many potentially protective compounds contained in plant-derived food are concentrated in the urine, it is plausible that bioactive agents in plants may play a role in bladder cancer chemoprevention. Flavokawain A is the predominant chalcone identified from kava root extract. The promise of flavokawain A is based on the following data : 1) an epidemiological study reported that high kava consumption correlated with lower incidences of cancers despite the presence of many smokers in the populations of the South Pacific Islands;2) In vitro cell culture studies showed that flavokawains but not kavalactones in kava extracts exhibited strong antiproliferative and apoptotic effects on human bladder cancer cells characterized as low- and high- grades;3) Flavokawain A inhibited tumor growth in xenograft models of superficial and invasive bladder cancer without any noticeable side effects;and 4) The chemical structure of flavokawain A, similar to some other chalcones, leads us to predict that it would cause no direct damage to DNA, bind to beta-tubulin, and induce phase II enzymes to protect against carcinogenesis. We hypothesize flavokawain A has chemopreventive effects on bladder epithelium via enhancing cell cycle regulation and increasing the sensitivity of apoptotic mechanisms. Three mouse models will be used to test this hypothesis: a carcinogen [4-hydroxybutyl (butyl) nitrosamine (OH-BBN)]-induced carcinogenesis model in mice bladders, and two spontaneous mouse bladder transgenic carcinogenesis models, each of which will address distinct issues. The OH-BBN model in mice will be used to examine flavokawain A's utility in primary prevention;for preventing the first occurrence of bladder cancer in those with risk factors such as cigarette smoking and industrial exposures. The transgenic models each induce a separate precursor state to advanced bladder cancer: either papillary tumors or carcinoma in situ, as seen in early stages of clinical bladder cancer. Examining flavokawain A in these transgenic models will provide information about its usefulness in secondary prevention, which clinically will address preventing bladder cancer recurrence and progression. Our microarray analysis has identified a few potential transcriptional targets (i.e. BIM, BID, survivin, Plk1, 14-3-3gamma, and SKP-2) for flavokawain A when inducing apoptosis and cell cycle arrests. We will validate these targets by examining their expression in vivo in these tested animal models and by using RNA interference and overexpression vectors to determine their contributions to flavokawain A's action in vitro, as well as by studying the down-stream events of these targets. Together, these studies will provide a firm answer to the promise of flavokawin A as a chemoprventative and/or chemotherapeutic agent.
Although bladder cancer is an ideal candidate for chemoprevention, the number of currently available chemopreventive agents is limited. We will examine the chemopreventive activities of a novel agent, flavokawain A, in a carcinogen [4-hydroxybutyl (butyl) nitrosamine (OH-BBN)]-induced mouse bladder carcinogenesis model, and two novel bladder transgenic mouse models each which induces a separate precursor state to advanced bladder cancer: either papillary transitional cell carcinoma or carcinoma in situ. In addition, we will validate potential transcriptional targets (i.e., BIM, BID, survivin, Plk1, 14-3-3gamma, and SKP-2) for flavokawain A-induced apoptosis and cell cycle arrests by examining their expression in vivo in these tested animal models and by using RNA interference and overexpression vectors to determine their contributions to flavokawain A's action in vitro.
|Liu, Zhongbo; Ha, U-Syn; Yu, Ke et al. (2017) Kavalactone yangonin induces autophagy and sensitizes bladder cancer cells to flavokawain A and docetaxel via inhibition of the mTOR pathway. J Biomed Res 31:408-418|
|Fu, Dong-Jun; Zhao, Ruo-Han; Li, Jia-Huan et al. (2017) Molecular diversity of phenothiazines: design and synthesis of phenothiazine-dithiocarbamate hybrids as potential cell cycle blockers. Mol Divers 21:933-942|
|Jandial, Danielle D; Krill, Lauren S; Chen, Lixia et al. (2017) Induction of G2M Arrest by Flavokawain A, a Kava Chalcone, Increases the Responsiveness of HER2-Overexpressing Breast Cancer Cells to Herceptin. Molecules 22:|
|Chen, Lixia; Xia, Guiyang; Qiu, Feng et al. (2016) Physapubescin selectively induces apoptosis in VHL-null renal cell carcinoma cells through down-regulation of HIF-2? and inhibits tumor growth. Sci Rep 6:32582|
|Ma, Yong-Cheng; Ke, Yu; Zi, Xiaolin et al. (2016) Induction of the mitochondria-mediated apoptosis in human esophageal cancer cells by DS2, a newly synthetic diterpenoid analog, is regulated by Bax and caused by generation of reactive oxygen species. Oncotarget 7:86211-86224|
|Chen, Li-Xia; Xia, Gui-Yang; He, Hao et al. (2016) New withanolides with TRAIL-sensitizing effect from Physalis pubescens L. RSC Adv 6:52925-52936|
|Liu, Zhongbo; Yokoyama, Noriko N; Blair, Christopher A et al. (2016) High Sensitivity of an Ha-RAS Transgenic Model of Superficial Bladder Cancer to Metformin Is Associated with ?240-Fold Higher Drug Concentration in Urine than Serum. Mol Cancer Ther 15:430-8|
|Zi, Xiaolin; Lusch, Achim; Blair, Christopher A et al. (2016) Effect of perineoplasm perinephric adipose tissues on migration of clear cell renal cell carcinoma cells: a potential role of WNT signaling. Oncotarget 7:53277-53288|
|Zhang, Saiyang; Li, Tingyu; Zhang, Yanbing et al. (2016) A new brominated chalcone derivative suppresses the growth of gastric cancer cells in vitro and in vivo involving ROS mediated up-regulation of DR5 and 4 expression and apoptosis. Toxicol Appl Pharmacol 309:77-86|
|Ma, Yong-Cheng; Su, Nan; Shi, Xiao-Jing et al. (2015) Jaridonin-induced G2/M phase arrest in human esophageal cancer cells is caused by reactive oxygen species-dependent Cdc2-tyr15 phosphorylation via ATM-Chk1/2-Cdc25C pathway. Toxicol Appl Pharmacol 282:227-36|
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