Original Article

Characterization of the anticancer effects of S115, a novel heteroaromatic thiosemicarbazone compound, in vitro and in vivo

Authors: Min-yu Liu, Lin Xiao, Yu-qiong Dong, Ying Liu, Li Cai, Wei-xia Xiong, Yu-long Yao, Ming Yin, Quan-hai Liu
DOI: 10.1038/aps.2014.71


Min-yu LIU1, 2, Lin XIAO2, Yu-qiong DONG3, Ying LIU2, Li CAI2, Wei-xia XIONG2, Yu-long YAO2, Ming YIN1, *, Quan-hai LIU2, *
1School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China; 2Department of Pharmacology, Shanghai Institute of Pharmaceutical Industry, Shanghai 200437, China; 3Shanghai Kairun Bio Pharm Company, Ltd, Shanghai 201108, China

Aim: To investigate the anticancer effects of S115, a novel heteroaromatic thiosemicarbazone compound in vitro and in vivo.
Methods: The anti-proliferative action of S115 was analyzed in 12 human and mouse cancer cell lines using MTT assay. Autograft and xenograft cancer models were made by subcutaneous inoculation of cancer cells into mice or nude mice. The mice were orally treated with S115 (2, 8, 32 mg·kg-1·d-1) for 7 d, and the tumor size was measured every 3 d. Cell apoptosis and cell cycle distribution were examined using flow cytometry, gene expression profile analyses, Western blots and RT-PCR.

Results: The IC50 values of S115 against 12 human and mouse cancer cell lines ranged from 0.3 to 6.6 μmol/L. The tumor growth inhibition rate caused by oral administration of S115 (32 mg·kg-1·d-1) were 89.7%, 81.7%, 78.4% and 77.8%, respectively, in mouse model of B16 melanoma, mouse model of Colon26 colon cancer, nude mouse model of A549 lung cancer and nude mouse model of SK-OV-3 ovarian cancer. Furthermore, oral administration of S115 (7.5 mg·kg-1·d-1) synergistically enhanced the anticancer effects of cyclophosphamide, cisplatin, or 5-fluorouracil in mouse model of S180 sarcoma. Treatment of A549 human lung cancer cells with S115 (1.5 μmol/L) induced G0/G1 cell cycle arrest, and increased apoptosis. Furthermore, S115 downregulated the level of ubiquitin, and upregulated the level of Tob2 in A549 cells.

Conclusion: S115 exerts anticancer effects against a variety of cancer cells in vitro and in grafted cancer models by inducing apoptosis, downregulating ubiquitin and upregulating Tob2.

Keywords: anticancer drug; thiourea; thiosemicarbazone; melanoma; colon cancer; human lung cancer; ovarian cancer; cell cycle arrest; apoptosis; ubiquitin; Tob2

This work was funded by the Biomedicine Scientific and Technological Projects of Shanghai (#10431900700). We thank Dr Yong-xiang WANG at Shanghai Jiao Tong University School of Pharmacy (Shanghai, China) for editing the manuscript.
* To whom correspondence should be addressed.
E-mail liuquanhai_lqh@163.com (Quan-hai LIU); myin@sjtu.edu.cn (Ming YIN)
Received 2014-03-06 Accepted 2014-06-25

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