ABSTRACT
Notch signaling has been identified as a critical pathway in gastric cancer (GC) progression and metastasis, and inhibition of Delta-like ligand 4 (DLL4), a Notch ligand, is suggested as a potent therapeutic approach for GC. Expression of both DLL4 and vascular endothelial growth factor receptor 2 (VEGFR2) was similar in the malignant tissues of GC patients. We focused on vascular endothelial growth factor (VEGF), a known angiogenesis regulator and activator of DLL4. Here, we used ABL001, a DLL4/VEGF bispecific therapeutic antibody, and investigated its therapeutic effect in GC. Treatment with human DLL4 therapeutic antibody (anti-hDLL4) or ABL001 slightly reduced GC cell growth in monolayer culture; however, they significantly inhibited cell growth in 3D-culture, suggesting a reduction in the cancer stem cell population. Treatment with anti-hDLL4 or ABL001 also decreased GC cell migration and invasion. Moreover, the combined treatment of irinotecan with anti-hDLL4 or ABL001 showed synergistic antitumor activity. Both combination treatments further reduced cell growth in 3D-culture as well as cell invasion. Interestingly, the combination treatment of ABL001 with irinotecan synergistically reduced the GC burden in both xenograft and orthotopic mouse models. Collectively, DLL4 inhibition significantly decreased cell motility and stem-like phenotype and the combination treatment of DLL4/VEGF bispecific therapeutic antibody with irinotecan synergistically reduced the GC burden in mouse models. Our data suggest that ABL001 potentially represents a potent agent in GC therapy. Further biochemical and pre-clinical studies are needed for its application in the clinic. [BMB Reports 2020; 53(10): 533-538].
Subject(s)
Intracellular Signaling Peptides and Proteins/metabolism , Membrane Proteins/metabolism , Stomach Neoplasms/metabolism , Vascular Endothelial Growth Factor A/metabolism , Adaptor Proteins, Signal Transducing/metabolism , Animals , Antibodies, Monoclonal/pharmacology , Calcium-Binding Proteins/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Female , Humans , Intercellular Signaling Peptides and Proteins/metabolism , Intracellular Signaling Peptides and Proteins/physiology , Irinotecan/pharmacology , Irinotecan/therapeutic use , Membrane Proteins/physiology , Mice, Inbred BALB C , Mice, Nude , Neoplastic Stem Cells/metabolism , Neovascularization, Pathologic/metabolism , Niacinamide/analogs & derivatives , Niacinamide/pharmacology , Pyrazoles/pharmacology , Signal Transduction/drug effects , Stomach Neoplasms/physiopathology , Vascular Endothelial Growth Factor A/physiology , Xenograft Model Antitumor AssaysABSTRACT
Delta-like-ligand 4 (DLL4) is a promising target to augment the effects of VEGF inhibitors. A simultaneous blockade of VEGF/VEGFR and DLL4/Notch signaling pathways leads to more potent anti-cancer effects by synergistic anti-angiogenic mechanisms in xenograft models. A bispecific antibody targeting VEGF and DLL4 (ABL001/NOV1501/TR009) demonstrates more potent in vitro and in vivo biological activity compared to VEGF or DLL4 targeting monoclonal antibodies alone and is currently being evaluated in a phase 1 clinical study of heavy chemotherapy or targeted therapy pre-treated cancer patients (ClinicalTrials.gov Identifier: NCT03292783). However, the effects of a combination of ABL001 and chemotherapy on tumor vessels and tumors are not known. Hence, the effects of ABL001, with or without paclitaxel and irinotecan were evaluated in human gastric or colon cancer xenograft models. The combination treatment synergistically inhibited tumor progression compared to each monotherapy. More tumor vessel regression and apoptotic tumor cell induction were observed in tumors treated with the combination therapy, which might be due to tumor vessel normalization. Overall, these findings suggest that the combination therapy of ABL001 with paclitaxel or irinotecan would be a better clinical strategy for the treatment of cancer patients.
Subject(s)
Adaptor Proteins, Signal Transducing/antagonists & inhibitors , Antibodies, Bispecific/pharmacology , Calcium-Binding Proteins/antagonists & inhibitors , Niacinamide/analogs & derivatives , Pyrazoles/pharmacology , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Animals , Antibodies, Bispecific/therapeutic use , Apoptosis/drug effects , Cell Line, Tumor , Disease Models, Animal , Disease Progression , Dose-Response Relationship, Drug , Drug Synergism , Humans , Mice , Neovascularization, Pathologic/drug therapy , Niacinamide/pharmacology , Niacinamide/therapeutic use , Pyrazoles/therapeutic use , Xenograft Model Antitumor AssaysABSTRACT
Steatosis is an established risk factor for disease progression in cases of chronic hepatitis C. Recently it was demonstrated that Hepatitis C virus (HCV) core and non-structural (NS) 2 proteins (NS2) induce lipid accumulation in hepatic cells. However, it has yet to be determined whether other HCV proteins are associated with lipid metabolism. The NS5A augmented the transcriptional activity and gene expression of PPARgamma. Furthermore, NS5A increased the ability to recruit the transcriptional coactivator PGC-1s to the PPRE with PPARgamma, as well as the interaction with PPARgamma2 and PGC-1alpha. Our results indicate that NS5A may exploit multiple strategies that enhance PPARgamma-induced lipid accumulation.
