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ORIGINAL RESEARCH article

Front. Chem. Biol.
Sec. Molecular Sciences
Volume 3 - 2024 | doi: 10.3389/fchbi.2024.1462351
This article is part of the Research Topic New Developments in Bioinorganic and Bioorganic Chemistry View all 4 articles

Acylfulvenes covalently interact with thioredoxin as additional cancer target

Provisionally accepted
Laura Slappendel Laura Slappendel 1Xiaodan Liu Xiaodan Liu 2*Michael R. MacArthur Michael R. MacArthur 3Charles M. Sharpless Charles M. Sharpless 4*Shana J. Sturla Shana J. Sturla 1*
  • 1 ETH Zürich, Zurich, Switzerland
  • 2 Max Planck Florida Institute for Neuroscience (MPFI), Jupiter, Florida, United States
  • 3 Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, United States
  • 4 Andlinger Center for Energy and the Environment, School of Engineering and Applied Science, Princeton University, Princeton, New Jersey, United States

The final, formatted version of the article will be published soon.

    Maintaining cellular redox homeostasis is critical for cell viability and growth, with disruptions implicated in cellular responses to chemicals and drugs. This study investigates the interactions between acylfulvenes (AFs), a class of DNA alkylating drugs, and thioredoxin (Trx), a key redox regulating enzyme. AFs are semi-synthetic derivatives of the natural product illudin S. While their cytotoxic properties are widely attributed to DNA alkylation, they also react with cellular thiols, such as Trx, and the implications of these interactions remain poorly understood. Through biochemical assays with isolated E. Coli Trx, and cellular experiments in a human cell line (HeLa), we elucidate AFs' impact on Trx activity and cellular levels. AFs, particularly hydroxymethylacylfulvene (HMAF), inhibited Trx activity by covalently modifying its active site cysteines.Drug exposure also altered cellular Trx levels and nuclear accumulation. In contrast, illudin S, which has a less selective toxicity profile for cancer cells, minimally inhibited isolated Trx. These data underscore Trx as a potential target contributing to the chemotherapeutic potential of AFs and provide insights into molecular interactions governing their impact on cancer cells.

    Keywords: drug metabolism, thioredoxin, Acylfulvene, Illudin S, Protein alkylation, anticancer drug, Protein degradation

    Received: 10 Jul 2024; Accepted: 26 Aug 2024.

    Copyright: © 2024 Slappendel, Liu, MacArthur, Sharpless and Sturla. 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) or licensor 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.

    * Correspondence:
    Xiaodan Liu, Max Planck Florida Institute for Neuroscience (MPFI), Jupiter, FL 33458, Florida, United States
    Charles M. Sharpless, Andlinger Center for Energy and the Environment, School of Engineering and Applied Science, Princeton University, Princeton, 08544, New Jersey, United States
    Shana J. Sturla, ETH Zürich, Zurich, Switzerland

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