title: Herbacetin Is a Novel Allosteric Inhibitor of Ornithine Decarboxylase with Antitumor Activity.
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.
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.|Biomedical Genomics Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon, 305-806, Korea.
authors.forename: Dong Joon
authors.initials: DJ
authors.lastname: Kim
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
authors.forename: Eunmiri
authors.initials: E
authors.lastname: Roh
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.|China-US Hormel Institute, Henan, 45008, China.
authors.forename: Mee-Hyun
authors.initials: MH
authors.lastname: Lee
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
authors.forename: Naomi
authors.initials: N
authors.lastname: Oi
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
authors.forename: Do Young
authors.initials: DY
authors.lastname: Lim
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.|Center for Laboratory Animal Resources, School of Animal Biotechnology, Kyungpook National University, Dae-gu, 700-842, Republic of Korea.
authors.forename: Myoung Ok
authors.initials: MO
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, College of Pharmacy, The Catholic University of Korea, Bucheon 420-743, Republic of Korea.
authors.forename: Young-Yeon
authors.initials: YY
authors.lastname: Cho
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
authors.forename: Angelo
authors.initials: A
authors.lastname: Pugliese
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.|College of Pharmacy, Mokpo National University, Muan-gun, Jeonnam 534-729, Republic of Korea.
authors.forename: Jung-Hyun
authors.initials: JH
authors.lastname: Shim
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
authors.forename: Hanyong
authors.initials: H
authors.lastname: Chen
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
authors.forename: Eun Jin
authors.initials: EJ
authors.lastname: Cho
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
authors.forename: Jong-Eun
authors.initials: JE
authors.lastname: Kim
authors.affiliation: Department of Biotechnology, Daegu University, Kyoungsan, Kyoungbook 712-714, Republic of Korea.
authors.forename: Sun Chul
authors.initials: SC
authors.lastname: Kang
authors.affiliation: Department of Biotechnology, Daegu University, Kyoungsan, Kyoungbook 712-714, Republic of Korea.
authors.forename: Souren
authors.initials: S
authors.lastname: Paul
authors.affiliation: Department of Pharmacology, College of Pharmacy, The Catholic University of Korea, Bucheon 420-743, Republic of Korea.
authors.forename: Hee Eun
authors.initials: HE
authors.lastname: Kang
authors.affiliation: Department of Pharmacology, College of Pharmacy, The Catholic University of Korea, Bucheon 420-743, Republic of Korea.
authors.forename: Ji Won
authors.initials: JW
authors.lastname: Jung
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
authors.forename: Sung-Young
authors.initials: SY
authors.lastname: Lee
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.|Center for Laboratory Animal Resources, School of Animal Biotechnology, Kyungpook National University, Dae-gu, 700-842, Republic of Korea.
authors.forename: Sung-Hyun
authors.initials: SH
authors.lastname: Kim
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
authors.forename: Kanamata
authors.initials: K
authors.lastname: Reddy
authors.affiliation: Biomedical Genomics Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon, 305-806, Korea.
authors.forename: Young Il
authors.initials: YI
authors.lastname: Yeom
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Bode
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D000518:Eflornithine / Q000494:pharmacology; D005260:Female; D005419:Flavonoids / Q000494:pharmacology* / Q000633:toxicity; D045325:HCT116 Cells; D034381:Hearing Loss / Q000139:chemically induced; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009955:Ornithine Decarboxylase / Q000737:chemistry / Q000378:metabolism; D065108:Ornithine Decarboxylase Inhibitors / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016588:Anticarcinogenic Agents; D000972:Antineoplastic Agents, Phytogenic; D005419:Flavonoids; D065108:Ornithine Decarboxylase Inhibitors; C581534:herbacetin; D009955:Ornithine Decarboxylase; D000518:Eflornithine