Mechanistic Insights into Photodynamic Regulation of Adenosine 5'-Triphosphate-Binding Cassette Drug Transporters.
Mechanistic Insights into Photodynamic Regulation of Adenosine 5'-Triphosphate-Binding Cassette Drug Transporters.
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DOI：
10.1021/acsptsci.1c00138
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发表时间：
2021-10-08
影响因子：
--
通讯作者：
Huang, Huang-Chiao
中科院分区：
文献类型：
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作者：
Liang, Barry J;Lusvarghi, Sabrina;Ambudkar, Suresh V;Huang, Huang-Chiao
通过抑制三磷酸腺苷结合盒（ABC）药物转运蛋白 ABCB1 和 ABCG2 来克服癌症多药耐药性的努力在临床上基本上失败了。无毒调节剂开发过程中面临的挑战表明需要从概念上转变为抑制 ABC 药物转运蛋白的新策略。在这里，我们揭示了利用光动力疗法（PDT）来操纵 ABC 药物转运蛋白的功能和完整性的基本机制。 PDT 是一种临床相关的、基于光化学的工具，涉及光敏剂的光激活以产生活性氧。 ATP 酶活性和计算机分子对接分析表明，光敏剂苯并卟啉衍生物 (BPD) 在无光情况下以微摩尔半最大抑制浓度与 ABCB1 和 ABCG2 结合。 BPD 的光激活产生单线态氧，以光学剂量依赖性方式进一步降低 ABCB1 和 ABCG2 的 ATPase 活性高达 12 倍。凝胶电泳和蛋白质印迹表明光激活的 BPD 通过共价交联诱导这些转运蛋白的聚集。我们提供了原理证明，证明 PDT 通过调节 ABCB1 和 ABCG2 转运蛋白的 ATP 酶活性和蛋白质完整性来影响这些转运蛋白的功能。从这项关于 ABC 药物转运蛋白光动力操纵的研究中获得的见解可能有助于开发和应用新的光学工具，以克服癌症化疗后经常出现的多药耐药性。
Efforts to overcome cancer multidrug resistance through inhibition of the adenosine triphosphate-binding cassette (ABC) drug transporters ABCB1 and ABCG2 have largely failed in the clinic. The challenges faced during the development of non-toxic modulators suggest a need for a conceptual shift to new strategies for the inhibition of ABC drug transporters. Here, we reveal the fundamental mechanisms by which photodynamic therapy (PDT) can be exploited to manipulate the function and integrity of ABC drug transporters. PDT is a clinically relevant, photochemistry-based tool that involves the light activation of photosensitizers to generate reactive oxygen species. ATPase activity and in silico molecular docking analyses show that the photosensitizer benzoporphyrin derivative (BPD) binds to ABCB1 and ABCG2 with micromolar half-maximal inhibitory concentrations in the absence of light. Light activation of BPD generates singlet oxygen to further reduce the ATPase activity of ABCB1 and ABCG2 by up to 12-fold in an optical dose-dependent manner. Gel electrophoresis and Western blotting revealed that light-activated BPD induces the aggregation of these transporters by covalent cross-linking. We provide a proof of principle that PDT affects the function of ABCB1 and ABCG2 by modulating the ATPase activity and protein integrity of these transporters. Insights gained from this study concerning the photodynamic manipulation of ABC drug transporters could aid in the development and application of new optical tools to overcome the multidrug resistance that often develops after cancer chemotherapy.