Iron-Dependent Cell Death: A New Treatment Approach against Pancreatic Ductal Adenocarcinoma
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Published:2023-10-07
Issue:19
Volume:24
Page:14979
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ISSN:1422-0067
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Container-title:International Journal of Molecular Sciences
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language:en
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Short-container-title:IJMS
Author:
Lopez-Blazquez Carlos1, Lacalle-Gonzalez Carlos2, Sanz-Criado Lara1, Ochieng’ Otieno Michael1, Garcia-Foncillas Jesus2, Martinez-Useros Javier13ORCID
Affiliation:
1. Translational Oncology Division, OncoHealth Institute, Health Research Institute—Fundación Jimenéz Diaz, Fundación Jimenéz Díaz University Hospital/Universidad Autónoma de Madrid (IIS-FJD/UAM), 28040 Madrid, Spain 2. Department of Medical Oncology, Fundación Jiménez Díaz University Hospital, 28040 Madrid, Spain 3. Area of Physiology, Department of Basic Health Sciences, Faculty of Health Sciences, Rey Juan Carlos University, 28922 Madrid, Spain
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a devastating tumor type where a very high proportion of people diagnosed end up dying from cancer. Surgical resection is an option for only about 20% of patients, where the 5-year survival increase ranges from 10 to 25%. In addition to surgical resection, there are adjuvant chemotherapy schemes, such as FOLFIRINOX (a mix of Irinotecan, oxaliplatin, 5-Fluorouraci and leucovorin) or gemcitabine-based treatment. These last two drugs have been compared in the NAPOLI-3 clinical trial, and the NALIRIFOX arm was found to have a higher overall survival (OS) (11.1 months vs. 9.2 months). Despite these exciting improvements, PDAC still has no effective treatment. An interesting approach would be to drive ferroptosis in PDAC cells. A non-apoptotic reactive oxygen species (ROS)-dependent cell death, ferroptosis was first described by Dixon et al. in 2012. ROS are constantly produced in the tumor cell due to high cell metabolism, which is even higher when exposed to chemotherapy. Tumor cells have detoxifying mechanisms, such as Mn-SOD or the GSH-GPX system. However, when a threshold of ROS is exceeded in the tumor cell, the cell’s antioxidant systems are overwhelmed, resulting in lipid peroxidation and, ultimately, ferroptosis. In this review, we point out ferroptosis as an approach to consider in PDAC and propose that altering the cellular ROS balance by combining oxidizing agents or with inhibitors of the main cellular detoxifiers triggers ferroptosis in PDAC.
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis
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