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

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.

MicroRNA-3163 targets ADAM-17 and enhances the sensitivity of hepatocellular carcinoma cells to molecular targeted agents

“…In addition, it confirmed that the miR-3163/ADAM-17 axis acts through the Notch signaling pathway. Therefore, our results indicated that miR-3163 may enhance the (1) Jia et al 49 used rhamnetin to inhibit the activation of the Notch signaling pathway and enhance the sensitivity of HCC cells to sorafenib by enhancing miR-34a, which targets Notch protein; (2) Zhang et al 50 identified a novel inhibitor of ADAM-17; and (3) the inhibitors of the presenilin-dependent gamma secretase complex may also be useful in the treatment of HCC [51][52][53][54] .…”

MicroRNA-645 targets urokinase plasminogen activator and decreases the invasive growth of MDA-MB-231 triple-negative breast cancer cells

“…The microtissues were adhered to the surface of the nude mice’s livers using biological-medical gel (Cai-Hong-Yi-Xue-She- Bei Corporation, Kunming City, Yunnan Province, People’s Republic of China). 44 , 45 After four to eight weeks of growth, the mice were harvested. The liver organs with nodules formed by the MDA-MB-231 cells were collected for Masson staining, following the methods described by Shao et al and Xie et al 46 , 47 The photographs of the Masson staining were quantitatively analyzed to determine the relative invasive growth of the MDA-MB-231 cells using the ImageJ software, following the methods descripted by Shao et al and Xie et al 46 – 48 The thickness of the nodules or liver organs was determined, and the relative invasive growth of the MDA-MB-231 cells in the nude mice’s livers (the nodule thickness relative to that of the liver organ) was calculated as follows: (the nodule thickness of the control group)/(the liver organ thickness of the control group) × 100% or (the nodule thickness of the administration group)/(the liver organ thickness of the administration group) × 100%.…”

<p>ARQ-197 enhances the antitumor effect of sorafenib in hepatocellular carcinoma cells via decelerating its intracellular clearance</p>

“…EMT process and HGF/c-MET pathway are foremost molecular mechanisms of antitumor drug resistance, which significantly promotes the antitumor effect of drugs on cancer cells. [67][68][69][70][71][72][73][74][75][76][77] Jiao et al showed that HGF treatment induced gefitinib resistance in human lung cancer cells and miR-1-3 p or miR-206 sensitizes cells to gefitinib by inhibition of c-Met and EMT process. 78 In the present work, we found that ARQ-197 inhibited the EMT process of HCC cells and enhanced the sensitivity of HCC cells to sorafenib.…”