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

Strusi, Gabriele, Suelzu, Caterina, Horwood, Nikki ORCID: https://orcid.org/0000-0002-6344-1677, Münsterberg, Andrea E. ORCID: https://orcid.org/0000-0002-4577-4240 and Bao, Yongping ORCID: https://orcid.org/0000-0002-6425-0370 (2023) Phenethyl isothiocyanate and dasatinib combination synergistically reduces hepatocellular carcinoma growth via cell cycle arrest and oxeiptosis. Frontiers in Pharmacology, 14. ISSN 1663-9812

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Abstract

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.

Item Type: Article
Additional Information: Funding information: This study was supported by Cancer and Prevention Research Trust London.
Uncontrolled Keywords: cancer therapeutics,oncology,drug development,oxeiptosis,combination therapy,dasatinib;,peitc,sdg 3 - good health and well-being,3* ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Faculty of Science > School of Biological Sciences
UEA Research Groups: Faculty of Science > Research Groups > Cells and Tissues
Faculty of Medicine and Health Sciences > Research Groups > Cancer Studies
Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health
Faculty of Medicine and Health Sciences > Research Centres > Lifespan Health
Depositing User: LivePure Connector
Date Deposited: 28 Sep 2023 09:30
Last Modified: 24 Dec 2023 02:54
URI: https://ueaeprints.uea.ac.uk/id/eprint/93123
DOI: 10.3389/fphar.2023.1264032

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