BODIPY-Caged Photoactivated Inhibitors of Cathepsin B Flip the Light Switch on Cancer Cell Apoptosis.,ACS Chemical Biology

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BODIPY-Caged Photoactivated Inhibitors of Cathepsin B Flip the Light Switch on Cancer Cell Apoptosis.
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2019-12-06 , DOI: 10.1021/acschembio.9b00711
Nicholas P Toupin ₁ , Karan Arora ₁ , Pradeep Shrestha ₂ , Julie A Peterson ₂ , Logan J Fischer ₂ , Erandi Rajagurubandara ₃ , Izabela Podgorski _{3,

4} , Arthur H Winter ₂ , Jeremy J Kodanko _{1,

4}

Affiliation

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 intracellular proteolytic networks on the minute time scale. Recent data indicate that CTSB inhibition may be a promising method to steer cells away from apoptotic death toward necrosis, a mechanism of cell death that can overcome resistance to apoptotic agents, stimulate an immune response and promote antitumor 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 entity. 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 noncancerous 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, this ability to trigger intracellular inactivation of CTSB with light provides researchers with a powerful photochemical tool for probing biochemical processes on short time scales.

中文翻译：

BODIPY-Caged 光激活组织蛋白酶 B 抑制剂可触发癌细胞凋亡的光开关。

获得性抗凋亡剂是癌症治疗中长期存在的挑战。组织蛋白酶 B (CTSB) 是一种酶，在许多基本功能中，通过在分钟时间尺度上调节细胞内蛋白水解网络，在细胞应激期间促进细胞凋亡。最近的数据表明，CTSB 抑制可能是一种很有前途的方法，可以引导细胞从凋亡死亡走向坏死，这是一种细胞死亡机制，可以克服对凋亡药物的抗性，刺激免疫反应并促进抗肿瘤免疫。不幸的是，CTSB 的快速和选择性细胞内失活是不可能的。然而，在这里，我们报告了 CTSB 的 BODIPY 笼状抑制剂的细胞渗透性的光化学和生物学特性的合成和表征，高度选择性，暴露于可见光后迅速激活。有趣的是，这些化合物显示出基于直接与硼结合的取代基的可调光物理和生物学特性。Me2BODIPY-caged 化合物 8 显示出光加速 CTSB 抑制和单个分子实体产生单线态氧的双重作用能力。8 的双重作用能力导致 MDA-MB-231 三阴性乳腺癌细胞的快速坏死反应，具有高光疗指数 (>30) 和对非癌细胞的选择性，CTSB 抑制和光敏化都不能单独提供。我们的工作证实，单线态氧产生和 CTSB 失活具有高度协同作用，是一种很有前途的杀死癌细胞的方法。此外，

更新日期：2019-12-07

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