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Phenethyl isothiocyanate and dasatinib combination synergistically reduces hepatocellular carcinoma growth via cell cycle arrest and oxeiptosis

Introduction: Hepatocellular carcinoma (HCC) is the most common type of liver cancer, which is among the most lethal tumours. Combination therapy exploits multiple drugs to target key pathways synergistically to reduce tumour growth. Isothiocyanates have been shown to possess anticancer potential an...

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Autores principales: Strusi, Gabriele, Suelzu, Caterina M., Horwood, Nicole, Münsterberg, Andrea E., Bao, Yongping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10583560/
https://www.ncbi.nlm.nih.gov/pubmed/37860118
http://dx.doi.org/10.3389/fphar.2023.1264032
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author Strusi, Gabriele
Suelzu, Caterina M.
Horwood, Nicole
Münsterberg, Andrea E.
Bao, Yongping
author_facet Strusi, Gabriele
Suelzu, Caterina M.
Horwood, Nicole
Münsterberg, Andrea E.
Bao, Yongping
author_sort Strusi, Gabriele
collection PubMed
description Introduction: Hepatocellular carcinoma (HCC) is the most common type of liver cancer, which is among the most lethal tumours. Combination therapy exploits multiple drugs to target key pathways synergistically to reduce tumour growth. Isothiocyanates have been shown to possess anticancer potential and to complement the anticancer activity of other compounds. This study aimed to investigate the potential of phenethyl isothiocyanate (PEITC) to synergise with dasatinib, improving its anticancer potential in HCC. Methods: MTT, 3D spheroids and clonogenic assays were used to assess the combination anti-tumour effect in vitro, whereas a murine syngeneic model was employed to evaluate the combination efficacy in vivo. DCFDA staining was employed to evaluate the production of reactive oxygen species (ROS), while flow cytometry and Western blot assays were used to elucidate the molecular mechanism of the synergistic activiy. Results: PEITC and dasatinib combination exhibited a synergistic effect in vitro and in vivo. The combination induced DNA damage and oxidative stress through the production of ROS, which led to the formation of a premature CDK1/Cyclin B1 complex associated with induction of mitotic catastrophe. Furthermore, ROS activated oxeiptosis, a caspase-independent form of programmed cell death. Conclusion: PEITC showed to enhance dasatinib action in treating HCC with increased production of ROS that induced cell cycle arrest followed by mitotic catastrophe, and to induce oxeiptosis. These results highlight the role that ITCs may have in cancer therapy as a complement of clinically approved chemotherapeutic drugs.
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spelling pubmed-105835602023-10-19 Phenethyl isothiocyanate and dasatinib combination synergistically reduces hepatocellular carcinoma growth via cell cycle arrest and oxeiptosis Strusi, Gabriele Suelzu, Caterina M. Horwood, Nicole Münsterberg, Andrea E. Bao, Yongping Front Pharmacol Pharmacology Introduction: Hepatocellular carcinoma (HCC) is the most common type of liver cancer, which is among the most lethal tumours. Combination therapy exploits multiple drugs to target key pathways synergistically to reduce tumour growth. Isothiocyanates have been shown to possess anticancer potential and to complement the anticancer activity of other compounds. This study aimed to investigate the potential of phenethyl isothiocyanate (PEITC) to synergise with dasatinib, improving its anticancer potential in HCC. Methods: MTT, 3D spheroids and clonogenic assays were used to assess the combination anti-tumour effect in vitro, whereas a murine syngeneic model was employed to evaluate the combination efficacy in vivo. DCFDA staining was employed to evaluate the production of reactive oxygen species (ROS), while flow cytometry and Western blot assays were used to elucidate the molecular mechanism of the synergistic activiy. Results: PEITC and dasatinib combination exhibited a synergistic effect in vitro and in vivo. The combination induced DNA damage and oxidative stress through the production of ROS, which led to the formation of a premature CDK1/Cyclin B1 complex associated with induction of mitotic catastrophe. Furthermore, ROS activated oxeiptosis, a caspase-independent form of programmed cell death. Conclusion: PEITC showed to enhance dasatinib action in treating HCC with increased production of ROS that induced cell cycle arrest followed by mitotic catastrophe, and to induce oxeiptosis. These results highlight the role that ITCs may have in cancer therapy as a complement of clinically approved chemotherapeutic drugs. Frontiers Media S.A. 2023-10-04 /pmc/articles/PMC10583560/ /pubmed/37860118 http://dx.doi.org/10.3389/fphar.2023.1264032 Text en Copyright © 2023 Strusi, Suelzu, Horwood, Münsterberg and Bao. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Strusi, Gabriele
Suelzu, Caterina M.
Horwood, Nicole
Münsterberg, Andrea E.
Bao, Yongping
Phenethyl isothiocyanate and dasatinib combination synergistically reduces hepatocellular carcinoma growth via cell cycle arrest and oxeiptosis
title Phenethyl isothiocyanate and dasatinib combination synergistically reduces hepatocellular carcinoma growth via cell cycle arrest and oxeiptosis
title_full Phenethyl isothiocyanate and dasatinib combination synergistically reduces hepatocellular carcinoma growth via cell cycle arrest and oxeiptosis
title_fullStr Phenethyl isothiocyanate and dasatinib combination synergistically reduces hepatocellular carcinoma growth via cell cycle arrest and oxeiptosis
title_full_unstemmed Phenethyl isothiocyanate and dasatinib combination synergistically reduces hepatocellular carcinoma growth via cell cycle arrest and oxeiptosis
title_short Phenethyl isothiocyanate and dasatinib combination synergistically reduces hepatocellular carcinoma growth via cell cycle arrest and oxeiptosis
title_sort phenethyl isothiocyanate and dasatinib combination synergistically reduces hepatocellular carcinoma growth via cell cycle arrest and oxeiptosis
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10583560/
https://www.ncbi.nlm.nih.gov/pubmed/37860118
http://dx.doi.org/10.3389/fphar.2023.1264032
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