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WTC ‐01, a novel synthetic oxime‐flavone compound, destabilizes microtubules in human nasopharyngeal carcinoma cells in vitro and in vivo
Author(s) -
Chiang ChangYing,
Wang TaiChi,
Lee ChoaHsun,
Chen ChienShu,
Wang ShihHao,
Lin YuChin,
Juang ShinHun
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13227
Subject(s) - tubulin , in vivo , colchicine , microtubule , apoptosis , chemistry , microbiology and biotechnology , cell growth , cancer cell , cell culture , in vitro , cancer research , biology , biochemistry , cancer , genetics
Background and Purpose 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. Experimental approach 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. Key Results WTC ‐01 was most potent against proliferation of NPC cells ( IC 50 = 0.45 μM), inducing accumulation of cells in G 2 /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 and Implications WTC ‐01, a new synthetic oxime‐containing flavone, exhibited potent anti‐tumour activity against NPC cells and merits further investigation.