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Abstract Title:

Herbacetin Is a Novel Allosteric Inhibitor of Ornithine Decarboxylase with Antitumor Activity.

Abstract Source:

Cancer Res. 2016 03 1 ;76(5):1146-1157. Epub 2015 Dec 16. PMID: 26676750

Abstract Author(s):

Dong Joon Kim, Eunmiri Roh, Mee-Hyun Lee, Naomi Oi, Do Young Lim, Myoung Ok Kim, Young-Yeon Cho, Angelo Pugliese, Jung-Hyun Shim, Hanyong Chen, Eun Jin Cho, Jong-Eun Kim, Sun Chul Kang, Souren Paul, Hee Eun Kang, Ji Won Jung, Sung-Young Lee, Sung-Hyun Kim, Kanamata Reddy, Young Il Yeom, Ann M Bode, Zigang Dong

Article Affiliation:

Dong Joon Kim

Abstract:

Ornithine decarboxylase (ODC) is a rate-limiting enzyme in the first step of polyamine biosynthesis that is associated with cell growth and tumor formation. Existing catalytic inhibitors of ODC have lacked efficacy in clinical testing or displayed unacceptable toxicity. In this study, we report the identification of an effective and nontoxic allosteric inhibitor of ODC. Using computer docking simulation and an in vitro ODC enzyme assay, we identified herbacetin, a natural compound found in flax and other plants, as a novel ODC inhibitor. Mechanistic investigations defined aspartate 44 in ODC as critical for binding. Herbacetin exhibited potent anticancer activity in colon cancer cell lines expressing high levels of ODC. Intraperitoneal or oral administration of herbacetin effectively suppressed HCT116 xenograft tumor growth and also reduced the number and size of polyps in a mouse model of APC-driven colon cancer (ApcMin/+). Unlike the well-established ODC inhibitor DFMO, herbacetin treatment was not associated with hearing loss. Taken together, our findings defined the natural product herbacetin as an allosteric inhibitor of ODC with chemopreventive and antitumor activity in preclinical models of colon cancer, prompting its further investigation in clinical trials.

Study Type : In Vitro Study

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Sayer Ji
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