2. Academic Validation
  3. Novel ADAM-17 inhibitor ZLDI-8 enhances the in vitro and in vivo chemotherapeutic effects of Sorafenib on hepatocellular carcinoma cells

Novel ADAM-17 inhibitor ZLDI-8 enhances the in vitro and in vivo chemotherapeutic effects of Sorafenib on hepatocellular carcinoma cells

  • Cell Death Dis. 2018 Jul 3;9(7):743. doi: 10.1038/s41419-018-0804-6.
Yingshi Zhang 1 2,  Dandan Li 1 2,  Qiyu Jiang 3,  Shuang Cao 4,  Huiwei Sun 3,  Yantao Chai 3,  Xiaojuan Li 3,  Tianshu Ren 1,  Ruichuang Yang 3,  Fan Feng 5,  Bo-An Li 6,  Qingchun Zhao 7 8
Affiliations

Affiliations

  • 1 Department of Pharmacy, General Hospital of Shenyang Military Area Command, Shenyang, 110840, China.
  • 2 Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China.
  • 3 Research Center For Clinical And Transitional Medicine, The 302nd Hospital of Chinese PLA, Beijing, 100039, China.
  • 4 Hubei Key Laboratory of Novel Chemical Reactor and Green Chemical Technology, Wuhan Institute of Technology, Wuhan, 430073, China.
  • 5 Center for Clinical Laboratory, The 302nd Hospital of Chinese PLA, Beijing, 100039, China. [email protected].
  • 6 Center for Clinical Laboratory, The 302nd Hospital of Chinese PLA, Beijing, 100039, China. [email protected].
  • 7 Department of Pharmacy, General Hospital of Shenyang Military Area Command, Shenyang, 110840, China. [email protected].
  • 8 Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China. [email protected].
PMID: 29970890 DOI: 10.1038/s41419-018-0804-6
Abstract

Hepatocellular carcinoma (HCC) is one of the greatest life threats for Chinese people, and the prognosis of this malignancy is poor due to the strong chemotherapy resistance in patients. Notch pathway components mediate cell survival and epithelial-mesenchymal transition (EMT), and also participate in the induction of multi-drug resistance (MDR). In the present study, we demonstrated the discovery of a novel inhibitor for Notch activating/cleaving Enzyme ADAM-17, named ZLDI-8; it inhibited the cleavage of Notch protein, consequently decreased the expression of pro-survival/anti-apoptosis and EMT related proteins. ZLDI-8 treatment enhanced the susceptibility of HCC cells to a small molecular kinase inhibitor Sorafenib, and chemotherapy agents Etoposide and Paclitaxel. ZLDI-8 treatment enhanced the effect of Sorafenib on inhibiting tumor growth in nude HCC-bearing mice model. These results suggest that ZLDI-8 can be a promising therapeutic agent to enhance Sorafenib's anti-tumor effect and to overcome the MDR of HCC patients.

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