Increased polyamine synthesis and inflammation are associated with intraepithelial neoplasia, which are risk factors for various types of cancer development in humans. Ornithine decarboxylase (ODC) is highly expressed in many cancer cell types and promotes growth and tumor formation. Elevated ODC activity in carcinogenesis model systems and neoplastic tissues suggests that this enzyme is a valid target for chemoprevention. Difluoromethylornithine (DFMO) is an approved FDA drug that acts as an irreversible and specific ODC inhibitor, and reportedly prevents carcinogenesis, especially in the skin and colon. However, high doses of DFMO in humans are associated with various degrees of hearing loss. By using computational biology with the BlueGene/L supercomputer, we have found at least one small molecule allosteric inhibitor of ODC that is less toxic and more potent than DFMO in suppressing skin and colon carcinogenesis. In this application, we propose to use state of the art technologies to identify and test additional novel, nontoxic small molecule inhibitors of ODC. These approaches include determining binding, binding affinities, specific binding sites and resulting structural changes by computation simulation using the BlueGene/L Supercomputer and our newly acquired GPU system, and performing protein binding assays, cell transformation assays and in vivo animal experiments, including the 2-stage mouse skin carcinogenesis model and the APCmin mouse model. Through these studies, we will develop more effective agents targeting ODC with fewer side effects for the chemoprevention of skin cancer and colon cancer.
Ornithine decarboxylase (ODC) is an enzyme that highly expressed in many cancer cell types and promotes growth and tumor formation. Difluoromethylornithine (DFMO) is an approved FDA drug that acts as an irreversible and specific ODC inhibitor and appears to prevent skin and colon. However, high doses of DFMO in humans cause hearing loss. Thus identifying new potent, nontoxic ODC inhibitors is extremely important.
|Zykova, Tatyana A; Zhu, Feng; Wang, Lei et al. (2017) The T-LAK Cell-originated Protein Kinase Signal Pathway Promotes Colorectal Cancer Metastasis. EBioMedicine 18:73-82|
|Chen, Lichan; Bode, Ann M; Dong, Zigang (2017) Circulating Tumor Cells: Moving Biological Insights into Detection. Theranostics 7:2606-2619|
|Gao, Ge; Zhang, Tianshun; Wang, Qiushi et al. (2017) ADA-07 Suppresses Solar Ultraviolet-Induced Skin Carcinogenesis by Directly Inhibiting TOPK. Mol Cancer Ther 16:1843-1854|
|Jin, Guoguo; Yao, Ke; Guo, Zhiping et al. (2017) APIO-EE-9 is a novel Aurora A and B antagonist that suppresses esophageal cancer growth in a PDX mouse model. Oncotarget 8:53387-53404|
|Sheng, Yuqiao; Liu, Kangdong; Wu, Qiong et al. (2016) PPMP, a novel tubulin-depolymerizing agent against esophageal cancer in patient-derived tumor xenografts. Oncotarget 7:30977-89|
|Kim, Dong Joon; Roh, Eunmiri; Lee, Mee-Hyun et al. (2016) Herbacetin Is a Novel Allosteric Inhibitor of Ornithine Decarboxylase with Antitumor Activity. Cancer Res 76:1146-1157|
|Hinchcliffe, Edward H; Day, Charles A; Karanjeet, Kul B et al. (2016) Chromosome missegregation during anaphase triggers p53 cell cycle arrest through histone H3.3 Ser31 phosphorylation. Nat Cell Biol 18:668-75|
|Peng, C; Zeng, W; Su, J et al. (2016) Cyclin-dependent kinase 2 (CDK2) is a key mediator for EGF-induced cell transformation mediated through the ELK4/c-Fos signaling pathway. Oncogene 35:1170-9|
|Kim, Jong-Eun; Kim, Jae Hwan; Lee, Younghyun et al. (2016) Bakuchiol suppresses proliferation of skin cancer cells by directly targeting Hck, Blk, and p38 MAP kinase. Oncotarget 7:14616-27|
|Bode, Ann M; Dong, Zigang; Wang, Hongyang (2016) Cancer prevention and control: alarming challenges in China. Natl Sci Rev 3:117-127|
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