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Cytotoxic Efficacy and Resistance Mechanism of a TRAIL and VEGFA-Peptide Fusion Protein in Colorectal Cancer Models
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Cytotoxic Efficacy and Resistance Mechanism of a TRAIL and VEGFA-Peptide Fusion Protein in Colorectal Cancer Models
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Cytotoxic Efficacy and Resistance Mechanism of a TRAIL and VEGFA-Peptide Fusion Protein in Colorectal Cancer Models
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Journal Article
Cytotoxic Efficacy and Resistance Mechanism of a TRAIL and VEGFA-Peptide Fusion Protein in Colorectal Cancer Models
2021
Overview
TNF-related apoptosis-inducing ligand (TRAIL) is a type II transmembrane protein capable of selectively inducing apoptosis in cancer cells by binding to its cognate receptors. Here, we examined the anticancer efficacy of a recently developed chimeric AD-O51.4 protein, a TRAIL fused to the VEGFA-originating peptide. We tested AD-O51.4 protein activity against human colorectal cancer (CRC) models and investigated the resistance mechanism in the non-responsive CRC models. The quantitative comparison of apoptotic activity between AD-O51.4 and the native TRAIL in nine human colorectal cancer cell lines revealed dose-dependent toxicity in seven of them; the immunofluorescence-captured receptor abundance correlated with the extent of apoptosis. AD-O51.4 reduced the growth of CRC patient-derived xenografts (PDXs) with good efficacy. Cell lines that acquired AD-O51.4 resistance showed a significant decrease in surface TRAIL receptor expression and apoptosis-related proteins, including Caspase-8, HSP60, and p53. These results demonstrate the effectiveness of AD-O51.4 protein in CRC preclinical models and identify the potential mechanism underlying acquired resistance. Progression of AD-O51.4 to clinical trials is expected.
Publisher
MDPI
Subject
/ Antineoplastic Agents - pharmacology
/ Apoptosis Regulatory Proteins - genetics
/ Apoptosis Regulatory Proteins - metabolism
/ Dose-Response Relationship, Drug
/ Drug Resistance, Neoplasm - drug effects
/ Humans
/ Mice
/ Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism
/ Recombinant Fusion Proteins - pharmacology
/ TNF-Related Apoptosis-Inducing Ligand - chemistry
/ TNF-Related Apoptosis-Inducing Ligand - genetics
/ TNF-Related Apoptosis-Inducing Ligand - metabolism
/ Vascular Endothelial Growth Factor A - chemistry
/ Vascular Endothelial Growth Factor A - genetics
