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.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Kim DJ,Roh E,Lee MH,Oi N,Lim DY,Kim MO,Cho YY,Pugliese A,Shim JH,Chen H,Cho EJ,Kim JE,Kang SC,Paul S,Kang HE,Jung JW,Lee SY,Kim SH,Reddy K,Yeom YI,Bode AM,Dong Zdoi
10.1158/0008-5472.CAN-15-0442subject
Has Abstractpub_date
2016-03-01 00:00:00pages
1146-1157issue
5eissn
0008-5472issn
1538-7445journal_volume
76pub_type
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