Therapeutic Potential of CUDC-907 (Fimepinostat) for Hepatocarcinoma Treatment Revealed by Tumor Spheroids-Based Drug Screening

被引:18
作者
Liao, Wei [1 ]
Yang, Wanren [1 ]
Xu, Jiecheng [1 ]
Yan, Zhengming [1 ]
Pan, Mingxin [1 ]
Xu, Xiaoping [1 ]
Zhou, Shuqin [2 ]
Zhu, Yu [3 ]
Lan, Jianqiang [3 ]
Zeng, Min [1 ]
Han, Xu [1 ]
Li, Shao [1 ]
Li, Yang [1 ]
Liang, Kangyan [1 ]
Gao, Yi [1 ,4 ]
Peng, Qing [1 ]
机构
[1] Southern Med Univ, Zhujiang Hosp,Guangzhou Clin Res & Transformat Ct, Guangdong Prov Res Ctr Artificial Organ & Tissue, Gen Surg Ctr,Dept Hepatobiliary Surg 2,Inst Regen, Guangzhou, Peoples R China
[2] Southern Med Univ, Zhujiang Hosp, Dept Anesthesiol, Guangzhou, Peoples R China
[3] Accurate Int Biotechnol Co, Guangzhou, Peoples R China
[4] Southern Med Univ, State Key Lab Organ Failure Res, Guangzhou, Peoples R China
基金
中国国家自然科学基金;
关键词
three-dimensional culture; drug screening; hepatocarcinoma; primary cells; CUDC-907 (fimepinostat); IN-VITRO; MYC; HDAC; INHIBITION; CULTURE; GROWTH; PI3K; HEPATOCYTES; COOPERATE; LYMPHOMA;
D O I
10.3389/fphar.2021.658197
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Background: Cancer is the second leading cause of death globally. However, most of the new anti-cancer agents screened by traditional drug screening methods fail in the clinic because of lack of efficacy. Choosing an appropriate in vitro tumor model is crucial for preclinical drug screening. In this study, we screened anti-hepatocarcinoma (HCC) drugs using a novel spheroid cell culture device.Methods: Four HCC cell lines were three-dimensionally (3D) cultured to screen 19 small molecular agents. 3D-cultured primary HCC cells and a tumor-bearing mouse model were used to verify the candidate anti-hepatocarcinoma agent. Cell function experiments and western blotting were conducted to explore the anti-hepatocarcinoma mechanism of the candidate agent.Results: We found that CUDC-907 can serve as a potent anti-hepatocarcinoma agent. The study data show that CUDC-907 (fimepinostat), a novel dual acting inhibitor of phosphoinositide 3-kinase (PI3K) and histone deacetylase (HDAC), has potent inhibitory effects on HCC cell lines and primary HCC cells in vitro, Animal studies have shown that CUDC-907 can also suppress HCC cells in vivo. Furthermore, we found that CUDC-907 inhibits the PI3K/AKT/mTOR pathway and downregulates the expression of c-Myc, leading to the suppression of HCC cells.Conclusion: Our results suggest that CUDC-907 can be a candidate anti-HCC drug, and the 3D in vitro drug screening method based on our novel spheroid culture device is promising for future drug screening efforts.
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页数:13
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