An Ethacrynic Acid‐Brominated BODIPY Photosensitizer (EA‐BPS) Construct Enhances the Lethality of Reactive Oxygen Species in Hypoxic Tumor‐Targeted Photodynamic Therapy
- 5 November 2020
- journal article
- research article
- Published by Wiley in Angewandte Chemie
- Vol. 60 (6), 3196-3204
- https://doi.org/10.1002/anie.202012687
Abstract
Despite being a clinically approved intervention for cancer, photodynamic therapy (PDT) still suffers from limitations. Prime among these is a therapeutic response that is mostly oxygen dependent. This limits the utility of PDT in treating hypoxic tumors since lower levels of cytotoxic reactive oxygen species (ROS) are generated in regions of low oxygen tension. Glutathione‐pi (GST‐pi) is a key enzyme that militates against ROS‐mediated apoptosis. We report here a new construct, EA‐BPS, that contains both a brominated BODIPY photosensitizer (BPS) and an ethacrynic acid (EA) GST‐pi inhibitor. Photoirradiation of EA‐BPS induces a synergistic antitumor effect that results from the combination of ROS production and GST‐pi inhibition. Relative to BPS alone, an enhanced cell‐killing effect is seen under hypoxic conditions both in vitro and in vivo. We conclude that by making better use of the available oxygen in tumor environments, improved therapeutic PDT outcomes should be achievable even under hypoxic conditions.Keywords
Funding Information
- National Research Foundation of Korea (2018R1A3B1052702 and NRF-2019M3E5D1A01068998, 2020R1A6A3A01100551, 2020R1A6A3A01100558)
- Welch Foundation (F-0018)
This publication has 70 references indexed in Scilit:
- Photoactivation switch from type II to type I reactions by electron-rich micelles for improved photodynamic therapy of cancer cells under hypoxiaJournal of Controlled Release, 2011
- The role of glutathione S-transferase P in signaling pathways and S-glutathionylation in cancerFree Radical Biology & Medicine, 2011
- Photodynamic therapy of cancer: An updateCA: A Cancer Journal for Clinicians, 2011
- Small Interfering RNA‐Mediated Silencing of Glutathione‐S‐Transferase A1 Sensitizes Hepatic Carcinoma Cells to Photodynamic Therapy with PentaphyrinsChemMedChem, 2008
- Detection of 2-hydroxyethidium in cellular systems: a unique marker product of superoxide and hydroethidineNature Protocols, 2007
- A review of the evidence supporting melatonin's role as an antioxidantJournal of Pineal Research, 1995
- Interactions of glutathione S-transferase-π with ethacrynic acid and its glutathione conjugateBiochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology, 1993
- Ethacrynic acid and its glutathione conjugate as inhibitors of glutathioneS-transferasesXenobiotica, 1993
- Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydesFree Radical Biology & Medicine, 1991
- Lysosomes, pH and the Anti-malarial Action of ChloroquineNature, 1972