期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 60, 期 6, 页码 3196-3204出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202012687
关键词
BODIPY; ethacrynic acid; glutathione S-transferase-pi; Hypoxia; photodynamic therapy
资金
- National Research Foundation of Korea (NRF) - Ministry of Science and ICT [2018R1A3B1052702, NRF-2019M3E5D1A01068998]
- Ministry of Education [2020R1A6A3A01100551, 2020R1A6A3A01100558]
- Department of Biotechnology, New Delhi [BT/RLF/Re-entry/59/2018]
- Robert A. Welch Foundation [F-0018]
This study introduces a new construct, EA-BPS, which induces a synergistic antitumor effect through a combination of ROS production and GST-π inhibition, leading to enhanced cell-killing effect under hypoxic conditions. By making better use of available oxygen in tumor environments, improved therapeutic PDT outcomes can be achieved even in low oxygen conditions.
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 herein 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.
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