Notch3 inhibition enhances sorafenib cytotoxic efficacy by promoting GSK3β phosphorylation and p21 down-regulation in hepatocellular carcinoma

Abstract

Sorafenib (Nexavar), a multiple kinase inhibitor, is the only clinically approved drug for patients with advanced HCC. However, its therapeutic success is limited by the emergence of drug resistance. Here we found that p21 and pGSK3βSer9 are major players in the resistance to sorafenib. We recently reported that aberrant Notch3 expression in HCC contributes to doxorubicin resistance in vitro and, therefore, we focused on the mechanisms that associate Notch3 to acquired drug resistance. In this study we first found that Notch3 inhibition significantly increased the apoptosis inducing effect of sorafenib in HCC cells via specific down-regulation of p21 and up-regulation of pGSK3βSer9. Using a mouse xenograft model we further found that Notch3 depletion combined with 21 days of sorafenib treatment exerts a substantial antitumor effect in vivo. Interestingly, we showed that, upon exposure to sorafenib treatment, Notch3 depleted xenografts maintain lower levels of p21 and higher levels of pGSK3βSer9 than control xenografts. Thus, this study demonstrated that inhibition of Notch3 signaling prevents HCC-mediate drug resistance and sensitizes HCC cells to sorafenib. Finally, we validated our in vitro and in vivo results in primary human HCCs showing that Notch3 protein expression positively correlated with p21 protein expression and negatively correlated with pGSK3βSer9 expression. In conclusion, the results presented in this study demonstrated that Notch3 silencing enhances the effect of sorafenib by overcoming drug resistance. Notch3 inhibition in combination with sorafenib can be a promising strategy for treatment of HCC.

Loss of Notch3 Signaling in Vascular Smooth Muscle Cells Promotes Severe Heart Failure Upon Hypertension

“…Given the deleterious effect of NOTCH3 activity in the development of pulmonary hypertension, 16 acute kidney disease, 36 and some cancers, 37,38 antagonists of NOTCH3 signaling have been considered as potential therapy. However, our data challenge the development of such therapeutic approach because the immediate cardiovascular impact could be disastrous similar to the cardiotoxic effects of antiangiogenic drugs, such as bevacizumab and sunitinib used in cancer therapy.…”

Trial Watch—Immunostimulation with cytokines in cancer therapy

“…Conversely, the combination of G-CSF with aggressive, multimodal chemotherapy was associated with severe side effects, resulting in the premature closure of the study. 98 The safety and efficacy of IFN-a2a and IFN-a2b have been evaluated in (1) five cohorts of 791, 365, 53, 51 and 40 subjects with advanced RCC, who received IFN-a2a in combination with the FDA-approved tumor-targeting antibody bevacizumab (which neutralizes vascular endothelial growth factor A, VEGFA) [121][122][123] (NCT00719264), along with the multitarget tyrosine kinase inhibitor sorafenib (UMIN000002466), 124,125 in the context of a multimodal treatment involving potentially immunogenic chemotherapy plus bevacizumab i.v. and low dose IL-2 s.c., [126][127][128] ; or optionally combined with a trophoblast glycoprotein (TPBG)-redirected variant of staphylococcal enterotoxin A (naptumomab estafenatox); 100,105,108,113,129 (2) 313 patients with symptomatic indolent B-cell lymphoma, receiving IFN-a2a in combination with the CD20-targeting mAb rituximab 130,131 99 Cumulatively, these studies confirm that IFNa2a and IFN-a2b can be safely administered to cancer patients as off-label indications.…”

Diosmetin triggers cell apoptosis by activation of the p53/Bcl-2 pathway and inactivation of the Notch3/NF-κB pathway in HepG2 cells

“…Notch3 regulates p53 at the post-transcriptional level by controlling both cyclin G1 expression and the cell signal transduction circuit, including microRNA-221 and mouse double minute 2 homolog in vitro and in vivo (16). Notch3 inhibition significantly increased the apoptosis effect induced by sorafenib in HCC cells via specific downregulation of p21 and upregulation of the phosphorylation of phospho-glycogen synthase kinase 3β Ser9 (17). …”