title: N-Hydroxycinnamide derivatives of osthole presenting genotoxicity and cytotoxicity against human colon adenocarcinoma cells in vitro and in vivo.
abstract: Osthole is extracted from the Chinese herbs Cnidium monnieri and Angelica pubescens, and it was found to have antitumor activity in vitro and in vivo. A series of osthole derivatives have been synthesized, and the N-hydroxycinnamide derivatives of osthole, WJ1376-1 and WJ1398-1 were found to have the greatest potential against human colon adenocarcinoma cells. In contrast to the parental osthole, both WJ1376-1 and WJ1398-1 were found to induce multinucleation and polyploidy by microscopic observation and flow cytometry. WJ1376-1 and WJ1398-1 significantly activated ataxia telangiectasia and rad3 related (ATR) kinase, which triggered activation of the checkpoint kinase 2 (Chk2) signaling pathway and then down regulated Cdc25 phosphatase and Cdc2/cyclin B kinase activities. WJ1376-1 and WJ1398-1 also inhibited the phosphorylation of Aurora A kinase, which is associated with important processes during mitosis. The presence of a "comet" DNA fragment and phosphorylation of p53 at Ser 15 clearly indicated that DNA damage occurred with WJ1376-1 and WJ1398-1 treatment. WJ1376-1 and WJ1398-1 ultimately induced apoptosis as evidenced by the upregulation of Bad and activation of caspases-3, -7, and -9. Furthermore, WJ1376-1 and WJ1398-1 also showed a great effect in attenuating tumor growth without affecting the body weight of xenograft nude mice. Taken together, these results suggest that the toxic activities of WJ1376-1 and WJ1398-1 were dissimilar to that of the parental osthole, which can induce cell polyploidy and G2/M cell cycle arrest in colon adenocarcinoma cells and may provide a potential therapeutic target for colon cancer treatment in the future.
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University , Taipei, Taiwan.
authors.forename: Ling-Yu
authors.initials: LY
authors.lastname: Liu
authors.forename: Wei-Jan
authors.initials: WJ
authors.lastname: Huang
authors.forename: Ren-Jye
authors.initials: RJ
authors.lastname: Lin
authors.forename: Shyr-Yi
authors.initials: SY
authors.lastname: Lin
authors.forename: Yu-Chih
authors.initials: YC
authors.lastname: Liang
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D003374:Coumarins / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity*; D004249:DNA Damage / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity*; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D003374:Coumarins; D006877:Hydroxamic Acids; C000588914:WJ1376-1; C000588915:WJ1398-1; D064007:Ataxia Telangiectasia Mutated Proteins; C046627:osthol