Study on the targeted therapy of oral squamous cell carcinoma with a plasmid expressing PE38KDEL toxin under control of the SERPINB3 promoter

Jing, Wu; Guo, Qiong; Zhang, Guoliang; Zhao, Liying; Lv, Yvguang; Wang, Jiaqi; Liu, Jiguang; Shi, Wei

doi:10.1002/cam4.2880

Cited by 7 publications

(2 citation statements)

References 28 publications

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“…Such chimeric molecules are called immunotoxins (ITs) ( 11 ). In the latter strategy, the coding sequence of a toxic protein is cloned under the control of a tumor-specific promoter and delivered to cancer cells ( 12 ). Tumor-specific promoters are derived from genes that are specifically and ectopically overexpressed in cancer cells ( 13 ).…”

Section: Introductionmentioning

confidence: 99%

Pseudomonas Exotoxin-Based Immunotoxins: Over Three Decades of Efforts on Targeting Cancer Cells With the Toxin

2021

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Cancer is one of the prominent causes of death worldwide. Despite the existence of various modalities for cancer treatment, many types of cancer remain uncured or develop resistance to therapeutic strategies. Furthermore, almost all chemotherapeutics cause a range of side effects because they affect normal cells in addition to malignant cells. Therefore, the development of novel therapeutic agents that are targeted specifically toward cancer cells is indispensable. Immunotoxins (ITs) are a class of tumor cell-targeted fusion proteins consisting of both a targeting moiety and a toxic moiety. The targeting moiety is usually an antibody/antibody fragment or a ligand of the immune system that can bind an antigen or receptor that is only expressed or overexpressed by cancer cells but not normal cells. The toxic moiety is usually a protein toxin (or derivative) of animal, plant, insect, or bacterial origin. To date, three ITs have gained Food and Drug Administration (FDA) approval for human use, including denileukin diftitox (FDA approval: 1999), tagraxofusp (FDA approval: 2018), and moxetumomab pasudotox (FDA approval: 2018). All of these ITs take advantage of bacterial protein toxins. The toxic moiety of the first two ITs is a truncated form of diphtheria toxin, and the third is a derivative of Pseudomonas exotoxin (PE). There is a growing list of ITs using PE, or its derivatives, being evaluated preclinically or clinically. Here, we will review these ITs to highlight the advances in PE-based anticancer strategies, as well as review the targeting moieties that are used to reduce the non-specific destruction of non-cancerous cells. Although we tried to be as comprehensive as possible, we have limited our review to those ITs that have proceeded to clinical trials and are still under active clinical evaluation.

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Section: Introductionmentioning

confidence: 99%

Pseudomonas Exotoxin-Based Immunotoxins: Over Three Decades of Efforts on Targeting Cancer Cells With the Toxin

2021

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“…SERPINB3 promoter activity was detected by luciferase assay and the suicide vector pSERPINB3-PE38KDEL was tested in the SERPINB3-positive TCA8113 cell line, and in the controls. Transfection of the pSERPINB3-PE38KDEL plasmid effectively inhibited cell proliferation and induced cell apoptosis, with no signifi-cant damage to MG63 and L02; however, a transwell invasion assay showed that significantly fewer TCA8113 cells than MG63 cells passed through the gel matrix following pSERPINB3-PE38KDEL transfection [37].…”

Section: Pseudomonas Exotoxin A/pe38-based Suicide Gene Therapy Appro...mentioning

confidence: 95%

From Immunotoxins to Suicide Toxin Delivery Approaches: Is There a Clinical Opportunity?

Ardini

Vago

Fabbrini

et al. 2022

Toxins

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Suicide gene therapy is a relatively novel form of cancer therapy in which a gene coding for enzymes or protein toxins is delivered through targeting systems such as vesicles, nanoparticles, peptide or lipidic co-adjuvants. The use of toxin genes is particularly interesting since their catalytic activity can induce cell death, damaging in most cases the translation machinery (ribosomes or protein factors involved in protein synthesis) of quiescent or proliferating cells. Thus, toxin gene delivery appears to be a promising tool in fighting cancer. In this review we will give an overview, describing some of the bacterial and plant enzymes studied so far for their delivery and controlled expression in tumor models.

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Study on the targeted therapy of oral squamous cell carcinoma with a plasmid expressing PE38KDEL toxin under control of the SERPINB3 promoter

et al. 2020

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Oral squamous cell carcinoma (OSCC) has a poor prognosis and a high risk of recurrence. To improve the efficacy of OSCC therapy, it is of great significance to explore gene therapy for OSCC. The use of specific genes to regulate the targeted expression of suicide genes is a hot topic in gene therapy for cancer. The SERPINB3 gene is highly active in squamous cell carcinoma, but nearly undetectable or present at a low level in normal tissues. This specificity suggests that the SERPINB3 promoter can be used for targeted OSCC therapy. Pseudomonas aeruginosa secretes PE38KDEL, an exotoxin derivative, as a suicide gene used in gene therapy. A SERPINB3 promoter‐mediated PE38KDEL expression vector was created. The SERPINB3 gene expression was tested in different cell lines by RT‐qPCR and Western blotting, and the SERPINB3 promoter activity was detected by luciferase assay. The SERPINB3 promoter was more active in the TCA8113 cell line than in the other cell lines. The target therapeutic potential of the toxin vector pSERPINB3‐PE38KDEL was tested in the SERPINB3‐positive TCA8113 cell line, the SERPINB3‐negative MG63 cell line, and normal L02 cell line. The SERPINB3 gene was expressed at a high level in TCA8113 cells but a low level in MG63 and L02 cells. Transfection of the pSERPINB3‐PE38KDEL plasmid effectively inhibited the proliferation and invasion of TCA8113 cells and induced cell apoptosis, but no significant damage to MG63 and L02 cells was observed. The results of in vitro experiments indicated that the pSERPINB3‐PE38KDEL plasmid could be a promising strategy for targeted OSCC gene therapy.

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Study on the targeted therapy of oral squamous cell carcinoma with a plasmid expressing PE38KDEL toxin under control of the SERPINB3 promoter

Cited by 7 publications

References 28 publications

Pseudomonas Exotoxin-Based Immunotoxins: Over Three Decades of Efforts on Targeting Cancer Cells With the Toxin

Pseudomonas Exotoxin-Based Immunotoxins: Over Three Decades of Efforts on Targeting Cancer Cells With the Toxin

From Immunotoxins to Suicide Toxin Delivery Approaches: Is There a Clinical Opportunity?

Study on the targeted therapy of oral squamous cell carcinoma with a plasmid expressing PE38KDEL toxin under control of the SERPINB3 promoter

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