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 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.
Original language | English |
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Pages (from-to) | 3196-3204 |
Number of pages | 9 |
Journal | Angewandte Chemie - International Edition |
Volume | 60 |
Issue number | 6 |
DOIs | |
Publication status | Published - 2021 Feb 8 |
Bibliographical note
Funding Information:This work was supported by the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (CRI project no. 2018R1A3B1052702 and NRF-2019M3E5D1A01068998, J.S.K.) and funded by the Ministry of Education (Basic Science Research Program 2020R1A6A3A01100551, M.W. and 2020R1A6A3A01100558, S.K.). A.S. thanks the Department of Biotechnology, New Delhi, for a prestigious Ramalingaswami Fellowship 2019 (Grant No. BT/RLF/Re-entry/59/2018). The Robert A. Welch Foundation (F-0018 to J.L.S.) is also acknowledged.
Funding Information:
This work was supported by the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (CRI project no. 2018R1A3B1052702 and NRF‐2019M3E5D1A01068998, J.S.K.) and funded by the Ministry of Education (Basic Science Research Program 2020R1A6A3A01100551, M.W. and 2020R1A6A3A01100558, S.K.). A.S. thanks the Department of Biotechnology, New Delhi, for a prestigious Ramalingaswami Fellowship 2019 (Grant No. BT/RLF/Re‐entry/59/2018). The Robert A. Welch Foundation (F‐0018 to J.L.S.) is also acknowledged.
Publisher Copyright:
© 2020 Wiley-VCH GmbH
Keywords
- BODIPY
- Hypoxia
- ethacrynic acid
- glutathione S-transferase-pi
- photodynamic therapy
ASJC Scopus subject areas
- Catalysis
- General Chemistry