title: WTC-01, a novel synthetic oxime-flavone compound, destabilizes microtubules in human nasopharyngeal carcinoma cells in vitro and in vivo.
abstract: OBJECTIVE
  Dynamic polymerization of microtubules is essential for cancer cell growth and metastasis, and microtubule-disrupting agents have become the most successful anti-cancer agents in clinical use. Besides their antioxidant properties, flavonoids also exhibit strong microtubule-disrupting activity and inhibit tumour growth. We have designed, synthesized and tested a series of oxime/amide-containing flavone derivatives. Here we report the evaluation of one compound, WTC-01 for its anti-proliferative effects in human cancer cells.
  
  
  METHODS
  We used a range of cancer cell lines including two human nasopharyngeal carcinoma (NPC) cell lines, measuring proliferation, cell cycle and apoptosis, along with caspase levels and mitochondrial membrane potentials. Assays of tubulin polymerisation in vitro and computer modelling of the colchicine binding site in tubulin were also used. In mice, pharmacokinetics and growth of NPC-derived tumours were studied.
  
  
  RESULTS
  WTC-01 was most potent against proliferation of NPC cells (IC50 = 0.45 μM), inducing accumulation of cells in G2 /M and increasing apoptosis, time- and concentration-dependently. The colchicine competition-binding experiments and computer modelling results suggested that WTC-01 causes microtubule disruption via binding to the colchicine-binding site of tubulin resulting in mitochondrial membrane damage and cell apoptosis via activation of caspase-9/-3 without noticeable activation of the caspase-8. Notably, our in vivo studies demonstrated that at doses of 25 and 50 mg·kg(-1) , WTC-01 exhibited good pharmacokinetic properties and completely inhibited the growth of NPC-TW01 cells in a xenograft nude mouse model.
  
  
  CONCLUSIONS
  WTC-01, a new synthetic oxime-containing flavone, exhibited potent anti-tumour activity against NPC cells and merits further investigation.
authors.affiliation: School of Pharmacy, China Medical University, Taichung, Taiwan.
authors.forename: Chang-Ying
authors.initials: CY
authors.lastname: Chiang
authors.affiliation: Department of Pharmacy, Tajen University, Pingtung, Taiwan.
authors.forename: Tai-Chi
authors.initials: TC
authors.lastname: Wang
authors.affiliation: School of Pharmacy, China Medical University, Taichung, Taiwan.
authors.forename: Choa-Hsun
authors.initials: CH
authors.lastname: Lee
authors.affiliation: School of Pharmacy, China Medical University, Taichung, Taiwan.
authors.forename: Chien-Shu
authors.initials: CS
authors.lastname: Chen
authors.affiliation: School of Pharmacy, China Medical University, Taichung, Taiwan.
authors.forename: Shih-Hao
authors.initials: SH
authors.lastname: Wang
authors.affiliation: School of Pharmacy, China Medical University, Taichung, Taiwan.
authors.forename: Yu-Chin
authors.initials: YC
authors.lastname: Lin
authors.affiliation: School of Pharmacy, China Medical University, Taichung, Taiwan.|Department of Pharmacy, Tajen University, Pingtung, Taiwan.|Department of Medical Research, China Medical University Hospital, Taichung, Taiwan.|Department of Pediatrics, Children's Hospital, China Medical University, Taichung, Taiwan.
authors.forename: Shin-Hun
authors.initials: SH
authors.lastname: Juang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002277:Carcinoma; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology*; D047309:Flavones / Q000494:pharmacology; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms; D010091:Oximes / Q000494:pharmacology*
chemical_list: C000608830:6-(2-hydroxyimino-2-(4-methoxyphenyl)ethoxy)-2-phenyl-4H-1-benzopyran-4-one; D000970:Antineoplastic Agents; D002867:Chromones; D047309:Flavones; D010091:Oximes; D020169:Caspases