Oncotarget

Research Papers:

WX-132-18B, a novel microtubule inhibitor, exhibits promising anti-tumor effects

Fang Guan, Rui Ding, Qi Zhang, Wei Chen, Feifei Li, Long Long, Wei Li, Linna Li, Dexuan Yang, Lan Xie, Shoujun Yuan and Lili Wang _

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Oncotarget. 2017; 8:71782-71796. https://doi.org/10.18632/oncotarget.17710

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Abstract

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

Correspondence to:

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

ABSTRACT

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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