WX-132-18B, a novel microtubule inhibitor, exhibits promising anti-tumor effects
Year: 2017
Type: article
Abstract: // Fang Guan 1, 2, * , Rui Ding 1, 2, * , Qi Zhang 3 , Wei Chen 1, 2 , Feifei Li 1, 2 , Long Long 1, 2 , Wei Li 1, 2 , Linna Li 3 , Dexuan Yang 3 , Lan Xie 1, 2 , Shoujun Yuan 3 and Lili Wang 1, 2 1 Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China 2 State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, 100850, China 3 Beijing 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 (IC 50 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.
Source: Oncotarget
Authors: Fang Guan, Rui Ding, Qi Zhang, Wei Chen, Feifei Li, Long Long, Wei Li, Linna Li, Dexuan Yang, Lan Xie, Shoujun Yuan, Lili Wang
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: diamond
OpenAlex ID: W2613375729