Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran 1435916471, Iran.
Molecular Biology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran 1435916471, Iran.
Toxins (Basel). 2021 Oct 22;13(11):749. doi: 10.3390/toxins13110749.
Hepatocellular carcinoma (HCC) is one of the high-metastatic types of cancer, and metastasis occurs in one-third of patients with HCC. To maintain the effectiveness of drug compounds on cancer cells and minimize their side effects on normal cells, it is important to use new approaches for overcoming malignancies. Immunotoxins (ITs), an example of such a new approach, are protein-structured compounds consisting of toxic and binding moieties which can specifically bind to cancer cells and efficiently induce cell death. Here, we design and scrutinize a novel immunotoxin against an oncofetal marker on HCC cells. We applied a truncated diphtheria toxin (DT389) without binding domain as a toxin moiety to be fused with a humanized YP7 scFv against a high-expressed Glypican-3 (GPC3) antigen on the surface of HCC cells. Cytotoxic effects of this IT were investigated on HepG2 (GPC3) and SkBr3 (GPC3) cell lines as positive- and negative-expressed GPC3 antigens. The dissociation constant (Kd) was calculated 11.39 nM and 18.02 nM for IT and YP7 scfv, respectively, whereas only IT showed toxic effects on the HepG2 cell line, and decreased cell viability (IC50 = 848.2 ng/mL). Changing morphology (up to 85%), cell cycle arrest at G2 phase (up to 13%), increasing intracellular reactive oxygen species (ROSs) (up to 50%), inducing apoptosis (up to 38% for apoptosis and 23% for necrosis), and an almost complete inhibition of cell movement were other effects of immunotoxin treatment on HepG2 cells, not on SkBr3 cell line. These promising results reveal that this new recombinant immunotoxin can be considered as an option as an HCC inhibitor. However, more extensive studies are needed to accomplish this concept.
肝细胞癌（HCC）是一种高转移性癌症类型，三分之一的 HCC 患者发生转移。为了保持药物化合物对癌细胞的有效性并最大程度地减少其对正常细胞的副作用，采用新方法克服恶性肿瘤至关重要。免疫毒素（IT）就是一种新方法的示例，它是由毒性和结合部分组成的蛋白质结构化合物，可以特异性结合癌细胞并有效地诱导细胞死亡。在这里，我们设计并研究了针对 HCC 细胞上的癌胚标志物的新型免疫毒素。我们应用了无结合域的截断白喉毒素（DT389）作为毒素部分，与针对 HCC 细胞表面高表达的 GPC3 抗原的人源化 YP7 scFv 融合。在 HepG2（GPC3）和 SkBr3（GPC3）细胞系中，研究了这种免疫毒素的细胞毒性作用，这两种细胞系均为高表达 GPC3 抗原的阳性和阴性表达细胞系。该 IT 的解离常数（Kd）分别为 11.39 nM 和 18.02 nM，而仅 IT 对 HepG2 细胞系表现出毒性作用，且降低细胞活力（IC50 = 848.2 ng/mL）。改变形态（高达 85％），细胞周期停滞在 G2 期（高达 13％），增加细胞内活性氧物质（ROS）（高达 50％），诱导细胞凋亡（凋亡高达 38％，坏死高达 23％），以及几乎完全抑制细胞运动，都是免疫毒素处理对 HepG2 细胞的其他作用，而对 SkBr3 细胞系则没有这些作用。这些有希望的结果表明，这种新型重组免疫毒素可以被认为是 HCC 抑制剂的一种选择。但是，需要进行更多的广泛研究来实现这一概念。
Zotero 插件
