Chiang Chang-Ying, Wang Tai-Chi, Lee Choa-Hsun, Chen Chien-Shu, Wang Shih-Hao, Lin Yu-Chin, Juang Shin-Hun
School of Pharmacy, China Medical University, Taichung, Taiwan.
Department of Pharmacy, Tajen University, Pingtung, Taiwan.
Br J Pharmacol. 2015 Oct;172(19):4671-83. doi: 10.1111/bph.13227. Epub 2015 Aug 14.
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.
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.
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.
WTC-01, a new synthetic oxime-containing flavone, exhibited potent anti-tumour activity against NPC cells and merits further investigation.
微管的动态聚合对于癌细胞的生长和转移至关重要，而微管破坏剂已成为临床上最成功的抗癌药物。除了具有抗氧化特性外，黄酮类化合物还表现出强大的微管破坏活性并抑制肿瘤生长。我们设计、合成并测试了一系列含肟/酰胺的黄酮衍生物。在此，我们报告一种化合物WTC - 01对人癌细胞增殖作用的评估。
我们使用了一系列癌细胞系，包括两个人鼻咽癌（NPC）细胞系，检测增殖、细胞周期、凋亡情况，以及半胱天冬酶水平和线粒体膜电位。还进行了体外微管蛋白聚合测定以及微管蛋白中秋水仙碱结合位点的计算机建模。在小鼠中，研究了药代动力学和NPC来源肿瘤的生长情况。
WTC - 01对NPC细胞的增殖最具抑制作用（IC50 = 0.45 μM），能时间和浓度依赖性地诱导细胞在G2 / M期积累并增加凋亡。秋水仙碱竞争结合实验和计算机建模结果表明，WTC - 01通过与微管蛋白的秋水仙碱结合位点结合导致微管破坏，进而通过激活半胱天冬酶 - 9 / - 3导致线粒体膜损伤和细胞凋亡，而半胱天冬酶 - 8无明显激活。值得注意的是，我们的体内研究表明，在25和50 mg·kg(-1) 的剂量下，WTC - 01表现出良好的药代动力学特性，并在异种移植裸鼠模型中完全抑制了NPC - TW01细胞的生长。
WTC - 01是一种新合成的含肟黄酮，对NPC细胞表现出强大的抗肿瘤活性，值得进一步研究。
