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BODIPY-Caged Photoactivated Inhibitors of Cathepsin B Flip the Light Switch on Cancer Cell Apoptosis
Authors
Karan Arora
Logan Fischer
+8 more
Jeremy Kodanko
Julie Peterson
Izabela Podgorski
Erandi Rajagurubandara
Pradeep Shrestha
Nicholas Toupin
Arthur Winter
Arthur Winter
Publication date
21 November 2019
Publisher
Abstract
Acquired resistance to apoptotic agents is a long-standing challenge in cancer treatment. Cathepsin B (CTSB) is an enzyme which, among many essential functions, promotes apoptosis during cellular stress through regulation of intracelllular proteolytic networks on the minute timescale. Recent data indicate that CTSB inhibition may be a promising method to steer cells away from apoptotic death towards necrosis, a mechanism of cell death that can overcome resistance to apoptotic agents, stimulate an immune response and promote anti-tumor immunity. Unfortunately, rapid and selective intracellular inactivation of CTSB has not been possible. However, here we report on the synthesis and characterization of photochemical and biological properties of BODIPY-caged inhibitors of CTSB that are cell permeable, highly selective and activated rapidly upon exposure to visible light. Intriguingly, these compounds display tunable photophysical and biological properties based on substituents bound directly to boron. Me2BODIPY-caged compound 8 displays the dual-action capability of light-accelerated CTSB inhibition and singlet oxygen production from a singular molecular entitiy. The dual-action capacity of 8 leads to a rapid necrotic response in MDA-MB-231 triple negative breast cancer cells with high phototherapeutic indexes (>30) and selectivity vs. non-cancerous cells that neither CTSB inhibition nor photosensitization gives alone. Our work confirms that singlet oxygen production and CTSB inactivation is highly synergistic and a promising method for killing cancer cells. Furthermore, our ability to trigger intracellular inactivation of CTSB with light will provide researchers with a powerful photochemical tool for probing biochemical processes on short timescales.This document is the unedited Author’s version of a Submitted Work that was subsequently accepted for publication in ACS Chemical Biology, copyright © American Chemical Society after peer review. To access the final edited and published work see DOI: 10.1021/acschembio.9b00711. Posted with permission.</p
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Last time updated on 11/01/2024