A small molecule inhibits protein disulfide isomerase and triggers the chemosensitization of cancer cells.

Abstract

Resistance to chemotherapeutic agents represents a major challenge in cancer research. One approach to this problem is combination therapy, the application of a toxic chemotherapeutic drug together with a sensitizing compound that addresses the vulnerability of cancer cells to induce apoptosis. Here we report the discovery of a new compound class (T8) that sensitizes various cancer cells towards etoposide treatment at subtoxic concentrations. Proteomic analysis revealed protein disulfide isomerase (PDI) as the target of the T8 class. In-depth chemical and biological studies such as the synthesis of optimized compounds, molecular docking analyses, cellular imaging, and apoptosis assays confirmed the unique mode of action through reversible PDI inhibition.

• Authors: Jürgen Eirich, Simone Braig, Liliana Schyschka, Phil Servatius, Judith Hoffmann, Sabrina Hecht, Simone Fulda, Stefan Zahler, Iris Antes, Uli Kazmaier, Stephan A Sieber, Angelika M Vollmar
• Journal: Angewandte Chemie (International ed. in English) (Angew Chem Int Ed Engl) Vol. 53 Issue 47 Pg. 12960-5 (Nov 17 2014) ISSN: 1521-3773 [Electronic] Germany
• PMID: 25256790 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Small Molecule Libraries
• Protein Disulfide-Isomerases

Topics

• Antineoplastic Agents (chemistry, pharmacology)
• Apoptosis (drug effects)
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Enzyme Inhibitors (chemistry, pharmacology)
• Humans
• Molecular Docking Simulation
• Molecular Structure
• Neoplasms (drug therapy, enzymology, pathology)
• Protein Disulfide-Isomerases (antagonists & inhibitors, metabolism)
• Proteomics
• Small Molecule Libraries (chemistry, pharmacology)
• Structure-Activity Relationship