WX-132-18B, a novel microtubule inhibitor, exhibits promising anti-tumor effects
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Fang Guan1,2,*, Rui Ding1,2,*, Qi Zhang3, Wei Chen1,2, Feifei Li1,2, Long Long1,2, Wei Li1,2, Linna Li3, Dexuan Yang3, Lan Xie1,2, Shoujun Yuan3 and Lili Wang1,2
1Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China
2State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, 100850, China
3Beijing Institute of Radiation Medicine, Beijing, 100850, China
*These authors have contributed equally to this work
Lili Wang, email: [email protected]
Shoujun Yuan, email: [email protected]
Keywords: tubulin inhibitor, anti-tumor effects, high content assay, cellular phenotype, colchicine-binding site
Received: November 16, 2016 Accepted: April 24, 2017 Published: May 09, 2017
Cancer drug researchers have been seeking microtubule-inhibiting agents (MIAs) with higher bioactivity and lower toxicity than currently marketed drugs. WX-132-18B, a novel structural compound synthesized at our institute, specifically bound to the colchicine-binding site on tubulin rather than the vinblastine site, and concentration-dependently reduced microtubule content via depolymerization. It exhibited the same cellular phenotypic profiles as the classic MIAs (colchicine, vincristine, and taxol), including inducing cell cycle arrest at the G2/M phase, triggering tumor cell apoptosis, promoting nuclear membrane permeability, reducing mitochondrial membrane potential, and disrupting the redox system balance. Importantly, WX-132-18B displayed more potent in vitro bioactivity (IC50 0.45–0.99 nM) than did the classic MIAs; it inhibited the proliferation of human umbilical vein endothelial cells and seven types of human tumor cells, especially the taxol-resistant breast cancer cells MX-1/T. WX-132-18B also dose-dependently inhibited mice sarcoma, human lung, and gastric cancer xenograft tumors and the formation of tumor blood vessels in mice. In conclusion, WX-132-18B is a novel microtubule-depolymerizing agent that selectively acts on the colchicine-binding site of tubulin and exerts potent in vitro and in vivo anti-tumor effects. These characteristics, along with its anti-angiogenesis and anti-drug resistance properties, make WX-132-18B a promising anti-tumor drug candidate.
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