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

作　　者：Min-yu LIU Lin XIAO Yu-qiong DONG Ying LIU Li CAI Wei-xia XIONG Yu-long YAO Ming YIN Quan-hai LIU 

机构地区：[1]School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China [2]Department of Pharmacology, Shanghai Institute of Pharmaceutical Industry, Shanghai 200437, China [3]Shanghai Kairun Bio Pharm Company, Ltd, Shanghai 201108, China

出　　处：《Acta Pharmacologica Sinica》2014年第10期1302-1310,共9页中国药理学报（英文版）

摘　　要：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 MIF 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 Sl15 （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 pmol/L. The tumor growth inhibition rate caused by oral administration of Sl15 （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 Sl15 （1.5 pmol/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.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 MIF 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 Sl15 （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 pmol/L. The tumor growth inhibition rate caused by oral administration of Sl15 （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 Sl15 （1.5 pmol/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.

关 键 词：anticancer drug THIOUREA THIOSEMICARBAZONE melanoma colon cancer human lung cancer ovarian cancer cell cyclearrest apoptosis UBIQUITIN Tob2 

分 类 号：Q255[生物学—细胞生物学] O641.4[理学—物理化学]