title: Novel antimitotic activity of 2-hydroxy-4-methoxy-2',3'-benzochalcone (HymnPro) through the inhibition of tubulin polymerization.
abstract: The natural chalcones and their derivatives exhibit many biological activities, such as anti-inflammatory and antitumoral. However, the precise mechanisms of action of benzochalcone derivatives are currently unknown. Here, a set of benzochalcones was synthesized, and the molecular mechanisms underlying inhibition of tumor growth were investigated. Colony-forming assays revealed that among tested compounds, 2-hydroxy-4-methoxy-2',3'-benzochalcone (HymnPro) most effectively inhibited the clonogenicity of Capan-1 human pancreatic cancer cells. HymnPro inhibited cell proliferation in several human solid tumor cell lines and suppressed xenografted tumor growth in nude mice. Mechanistically, HymnPro induced cell cycle arrest at the G2/M phase, followed by an increase in apoptotic cell death. These events were associated with the inhibition of tubulin polymerization through binding of HymnPro to tubulin, leading to the formation of abnormal mono- or multipolar mitotic microtubule structures accompanied by spherical arrangement of multinucleated chromosomes. Furthermore, HymnPro activated caspase-2, caspase-9, caspase-3, and caspase-7 and increased the cleavage of poly(ADP-ribose) polymerase (PARP). HymnPro increased the phosphorylation of JNK1/2, Erk1/2, and p38 kinase. Pretreatment with SP600125, U0126, or SB600125 abrogated HymnPro-induced activation of caspases-3 and caspase-7 and the cleavage of PARP, suggesting that MAPK signalings are involved in HymnPro-induced apoptosis. It was concluded that a novel HymnPro compound exerts antitumor activity by disrupting microtubule assembly, which leads to mitotic arrest and sequential activation of the caspase pathway, resulting in apoptosis.
authors.affiliation: Department of Biological Sciences, College of Biological Science and Biotechnology, Cancer and Metabolism Institute, Konkuk University , Seoul 143-701, Republic of Korea.
authors.forename: Soon Young
authors.initials: SY
authors.lastname: Shin
authors.forename: Ji-Ho
authors.initials: JH
authors.lastname: Kim
authors.forename: Hyuk
authors.initials: H
authors.lastname: Yoon
authors.forename: Yang-Kyu
authors.initials: YK
authors.lastname: Choi
authors.forename: Dongsoo
authors.initials: D
authors.lastname: Koh
authors.forename: Yoongho
authors.initials: Y
authors.lastname: Lim
authors.forename: Young Han
authors.initials: YH
authors.lastname: Lee
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002599:Chalcone / Q000737:chemistry / Q000494:pharmacology*; D006131:Growth Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008938:Mitosis / Q000187:drug effects*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000503:physiopathology*; D058105:Polymerization / Q000187:drug effects; D014404:Tubulin / Q000737:chemistry* / Q000378:metabolism
chemical_list: D006131:Growth Inhibitors; D014404:Tubulin; D002599:Chalcone