5-(Furan-2-yl)-4-(3,4,5-trimethoxyphenyl)-3H-1,2-dithiol-3-one oxime (6f), a new synthetic compound, causes human ﬁbrosarcoma HT-1080 cell apoptosis by disrupting tubulin polymerisation and inducing G2/M arrest

Zuo,Daiying; Pang,Lili; Shen,Jiwei; Guan,Qi; Bai,Zhaoshi; Zhang,Huijuan; Li,Yao; Lu,Guodong; Zhang,Weige; Wu,Yingliang

doi:10.3892/ijo.2017.3963

5-(Furan-2-yl)-4-(3,4,5-trimethoxyphenyl)-3H-1,2-dithiol-3-one oxime (6f), a new synthetic compound, causes human ﬁbrosarcoma HT-1080 cell apoptosis by disrupting tubulin polymerisation and inducing G2/M arrest

Authors:
- Daiying Zuo
- Lili Pang
- Jiwei Shen
- Qi Guan
- Zhaoshi Bai
- Huijuan Zhang
- Yao Li
- Guodong Lu
- Weige Zhang
- Yingliang Wu
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Affiliations: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, P.R. China, Department of Clinical Pharmacy, The Sixth People's Hospital of Chengdu, Chengdu, Sichuan 610051, P.R. China, Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, P.R. China
Published online on: April 18, 2017 https://doi.org/10.3892/ijo.2017.3963
Pages: 2069-2078

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Abstract

In the current study, we synthesized a series of new compounds targeting tubulin and tested their anti-proliferative activities. Among these new synthetic compounds, 5-(furan-2-yl)-4-(3,4,5-trimethoxyphenyl)-3H-1,2-dithiol-3-one oxime (6f) exhibited significant anti-proliferative activity against different human cancer cell lines including human gastric adenocarcinoma SGC-7901, human non-small cell lung cancer A549, and human ﬁbrosarcoma HT-1080. As a result, 6f was selected to further test the sensitivity to different cancer cell lines including human cervical cancer cell line HeLa, human breast cancer cell line MCF-7, non-small cell lung cancer cell line A549, human liver carcinoma cell line HepG-2, human oral squamous cell carcinoma cell lines KB, SGC-7901 and HT-1080. Among these cell lines, HT-1080 and HeLa are the most sensitive. Therefore, HT-1080 was selected to further explore the properties of anti-proliferative activity and the underlying mechanisms. Our data proved that 6f exhibited strong anti-proliferative effects against HT-1080 cells in a time- and dose-dependent manner. We showed that the growth inhibitory effect of 6f in HT-1080 cells was related with microtubule depolymerisation. Molecular docking studies revealed that 6f interacted and bound efﬁciently with the colchicine-binding site of tubulin. In addition, 6f treatment induced G2/M cell cycle arrest dose-dependently and subsequently induced cell apoptosis. Western blot study indicated that upregulation of cyclin B1 and p-cdc2 was related with G2/M arrest. 6f-induced cell apoptosis was associated with both mitochondrial and death receptor pathway. In conclusion, our data showed that 6f, among the newly synthetic compounds, exhibited highest anti-proliferative activity by disrupting the microtubule polymerisation, causing G2/M arrest and subsequently inducing cell apoptosis in HT-1080 cells. Hence, 6f is a promising microtubule depolymerising agent for the treatment of various cancers especially human ﬁbrosarcoma.

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