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Factor VII light chain-targeted lidamycin shows intensified therapeutic efficacy for liver cancer
Qing Zhang1, Xiujun Liu, Shuangshuang Xu
1Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical College, Xuzhou, PR China. qingzhang_btc@sina.com
Abstract:
The overexpression of tissue factor (TF) observed in numerous cancer cells and clinical samples of human cancers makes TF an ideal target for cancer therapy. The purpose of this study is to develop a TF-targeting energized fusion protein hlFVII-LDP-AE, which is composed of a human Factor VII light chain (hlFVII) as the targeting domain conjugated to the cytotoxic antibiotic lidamycin (LDM, LDP-AE) as the effector domain. The potential efficacy of hlFVII-LDP-AE for cancer therapy was tested in vitro by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and colony formation assays and in vivo with a BALB/c nude mouse xenograft model of human liver cancer line HepG2. The inhibitory concentration (IC(50)) value of hlFVII-LDP-AE varied from 0.15 to 0.64 nM for the various human tumor lines. hlFVII-LDP-AE showed a tumor growth inhibition rate of 90.6% at the dose of 0.6 mg/kg in in vivo animal experiments. The mechanism through which hlFVII-LDP-AE inhibits tumor growth also was determined by Hoechst 33342 staining and Tdt-mediated dUTP nick-end labeling (TUNEL) assay. hlFVII-LDP-AE causes tumor cell death through inducing chromatin condensation and cleavage of genomic DNA. These findings suggest that the hlFVII-LDP-AE protocol is efficacious and tolerated in the mouse model of human liver cancer HepG2 and has clinical applicability for treating cancer patients.
Insights
A novel fusion protein, hlFVII-LDP-AE, targets tissue factor (TF) for cancer therapy. This engineered protein effectively inhibited liver cancer growth in mice by inducing cancer cell death, showing clinical potential.
Area of Science:
- Oncology
- Molecular Biology
- Biotechnology
Background:
- Tissue Factor (TF) is overexpressed in many cancers, making it a promising therapeutic target.
- Developing targeted therapies can improve treatment efficacy and reduce side effects.
Purpose of the Study:
- To create and evaluate a novel TF-targeting fusion protein, hlFVII-LDP-AE, for cancer treatment.
- To assess the in vitro and in vivo efficacy of hlFVII-LDP-AE against human liver cancer.
Main Methods:
- Fusion protein construction: human Factor VII light chain (hlFVII) linked to lidamycin (LDM/LDP-AE).
- In vitro efficacy testing using MTT and colony formation assays on human tumor lines.
- In vivo evaluation in a BALB/c nude mouse xenograft model using human liver cancer HepG2 cells.
Main Results:
- hlFVII-LDP-AE demonstrated potent cytotoxicity with IC(50) values ranging from 0.15 to 0.64 nM against tumor lines.
- A significant tumor growth inhibition rate of 90.6% was observed in vivo at a dose of 0.6 mg/kg.
- Mechanism of action confirmed: induction of chromatin condensation and genomic DNA cleavage leading to tumor cell death.
Conclusions:
- The hlFVII-LDP-AE fusion protein is an effective and well-tolerated therapeutic agent in a preclinical liver cancer model.
- This TF-targeted therapy shows promise for clinical application in treating human cancers.
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