DT389-YP7, a Recombinant Immunotoxin against Glypican-3 That Inhibits Hepatocellular Cancer Cells: An In Vitro Study

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...

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Autores principales:	Hamid Hashemi Yeganeh, Mohammad Heiat, Marek Kieliszek, Seyed Moayed Alavian, Ehsan Rezaie
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	Glypican-3 hepatocellular carcinoma humanized YP7 diphtheria toxin new recombinant immunotoxin Medicine R
Acceso en línea:	https://doaj.org/article/2e5e1fe43e934ac890c9e94c1a657670
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spelling	oai:doaj.org-article:2e5e1fe43e934ac890c9e94c1a6576702021-11-25T19:08:32ZDT389-YP7, a Recombinant Immunotoxin against Glypican-3 That Inhibits Hepatocellular Cancer Cells: An In Vitro Study10.3390/toxins131107492072-6651https://doaj.org/article/2e5e1fe43e934ac890c9e94c1a6576702021-10-01T00:00:00Zhttps://www.mdpi.com/2072-6651/13/11/749https://doaj.org/toc/2072-6651Hepatocellular 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<sup>+</sup>) and SkBr3 (GPC3<sup>−</sup>) 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.Hamid Hashemi YeganehMohammad HeiatMarek KieliszekSeyed Moayed AlavianEhsan RezaieMDPI AGarticleGlypican-3hepatocellular carcinomahumanized YP7diphtheria toxinnew recombinant immunotoxinMedicineRENToxins, Vol 13, Iss 749, p 749 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Glypican-3 hepatocellular carcinoma humanized YP7 diphtheria toxin new recombinant immunotoxin Medicine R
spellingShingle	Glypican-3 hepatocellular carcinoma humanized YP7 diphtheria toxin new recombinant immunotoxin Medicine R Hamid Hashemi Yeganeh Mohammad Heiat Marek Kieliszek Seyed Moayed Alavian Ehsan Rezaie DT389-YP7, a Recombinant Immunotoxin against Glypican-3 That Inhibits Hepatocellular Cancer Cells: An In Vitro Study
description	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<sup>+</sup>) and SkBr3 (GPC3<sup>−</sup>) 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.
format	article
author	Hamid Hashemi Yeganeh Mohammad Heiat Marek Kieliszek Seyed Moayed Alavian Ehsan Rezaie
author_facet	Hamid Hashemi Yeganeh Mohammad Heiat Marek Kieliszek Seyed Moayed Alavian Ehsan Rezaie
author_sort	Hamid Hashemi Yeganeh
title	DT389-YP7, a Recombinant Immunotoxin against Glypican-3 That Inhibits Hepatocellular Cancer Cells: An In Vitro Study
title_short	DT389-YP7, a Recombinant Immunotoxin against Glypican-3 That Inhibits Hepatocellular Cancer Cells: An In Vitro Study
title_full	DT389-YP7, a Recombinant Immunotoxin against Glypican-3 That Inhibits Hepatocellular Cancer Cells: An In Vitro Study
title_fullStr	DT389-YP7, a Recombinant Immunotoxin against Glypican-3 That Inhibits Hepatocellular Cancer Cells: An In Vitro Study
title_full_unstemmed	DT389-YP7, a Recombinant Immunotoxin against Glypican-3 That Inhibits Hepatocellular Cancer Cells: An In Vitro Study
title_sort	dt389-yp7, a recombinant immunotoxin against glypican-3 that inhibits hepatocellular cancer cells: an in vitro study
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/2e5e1fe43e934ac890c9e94c1a657670
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DT389-YP7, a Recombinant Immunotoxin against Glypican-3 That Inhibits Hepatocellular Cancer Cells: An In Vitro Study

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