Repurposing Sulfasalazine as a Radiosensitizer in Hypoxic Human Colorectal Cancer

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Abstract

xCT overexpression in cancer cells has been linked to tumor growth, metastasis and treatment resistance. Sulfasalazine (SSZ), an FDA-approved drug for the treatment of rheumatoid sarthritis, and inflammatory bowel diseases, has anticancer properties via inhibition of xCT, leading to the disruption of redox homeostasis. Since reactive oxygen species (ROS) are pivotal for the efficacy of radiotherapy (RT), elevated levels of ROS are associated with improved RT outcomes. In this study, the influence of SSZ treatment on the radiosensitivity of human colorectal cancer (CRC) cells was investigated. Our principal finding in human HCT116 and DLD-1 cells was that SSZ enhances the radiosensitivity of hypoxic CRC cells but does not alter the intrinsic radiosensitivity. The radiosensitizing effect was attributed to the depletion of glutathione and thioredoxin reductase levels. In turn, the reduction leads to excessive levels of ROS, increased DNA damage, and ferroptosis induction. Confirmation of these findings was performed in 3D models and in DLD-1 xenografts. Taken together, this study is a stepping stone for applying SSZ as a radiosensitizer in the clinic and confirms that xCT in cancer cells is a valid radiobiological target.
Translated title of the contributionRepurposing Sulfasalazine as a Radiosensitizer in Hypoxic Human Colorectal Cancer
Original languageEnglish
Article number2363
JournalCancers
Volume15
Issue number8
DOIs
Publication statusPublished - 18 Apr 2023

Bibliographical note

Funding Information:
This work was supported by a personal one-year Emmanuel van der Schueren PhD scholarship awarded to LK by Kom Op Tegen Kanker (non-governmental organization, Belgium) and a Strategic Research Program from the Vrije Universiteit Brussel (SRP53).

Publisher Copyright:
© 2023 by the authors.

Copyright:
Copyright 2023 Elsevier B.V., All rights reserved.

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