title: New 2-aryl-1,4-naphthoquinone-1-oxime methyl ether compound induces microtubule depolymerization and subsequent apoptosis.
abstract: In this study, we describe the antitumor activity of QO-1, one of the new 2-aryl-1,4-naphthoquinone-1-oxime methyl ether derivatives. QO-1 is a derivative of macarpine, a natural occurring product from Rutaceae plant. It could potently inhibit cell growth when tested on 19 cancer cell lines. To investigate its mechanism, two cell lines (HeLa and MCF-7) sensitive to QO-1 were selected. Based on flow cytometry, it was found to induce G(2)/M-phase arrest. Moreover, it could cause microtubule depolymerization both in vitro and in vivo. On the other hand, QO-1 activated spindle assembly checkpoint (SAC) proteins. Expression of Bub1, one of the SAC, was gradually increased, reaching a peak after 16 - 20 h, and then gradually decreased. Instead, QO-1 increased the sub-G(1) population, which suggested a cell death population. Actually, expression of Bcl-2 family proteins and activation of caspase-3/7 were evidences of apoptosis. Consistent with these results, cells with DNA fragmentation and multinucleated cells were increased time-dependently after QO-1 exposure. In conclusion, QO-1 has promising antitumor effects via microtubule depolymerization.
authors.affiliation: Department of Geriatric Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Chiba University, Japan. hiromi-s@chiba-u.jp
authors.forename: Hiromi
authors.initials: H
authors.lastname: Sato
authors.forename: Ryota
authors.initials: R
authors.lastname: Yamada
authors.forename: Midori
authors.initials: M
authors.lastname: Yanagihara
authors.forename: Hiroko
authors.initials: H
authors.lastname: Okuzawa
authors.forename: Hiroki
authors.initials: H
authors.lastname: Iwata
authors.forename: Ayako
authors.initials: A
authors.lastname: Kurosawa
authors.forename: Saki
authors.initials: S
authors.lastname: Ichinomiya
authors.forename: Rina
authors.initials: R
authors.lastname: Suzuki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Okabe
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Yano
authors.forename: Takuya
authors.initials: T
authors.lastname: Kumamoto
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Suzuki
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Ishikawa
authors.forename: Koichi
authors.initials: K
authors.lastname: Ueno
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D053938:DNA Fragmentation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D008738:Methyl Ethers / Q000737:chemistry / Q000494:pharmacology; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D009285:Naphthoquinones / Q000737:chemistry* / Q000494:pharmacology*; D050257:Tubulin Modulators / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D008738:Methyl Ethers; D009285:Naphthoquinones; D050257:Tubulin Modulators; C035342:1,4-naphthoquinone