Dual Inhibition of Pyruvate Dehydrogenase Complex and Respiratory Chain Complex Induces Apoptosis by a Mitochondria-Targeted Fluorescent Organic Arsenical in vitro and in vivo.,ChemMedChem

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Dual Inhibition of Pyruvate Dehydrogenase Complex and Respiratory Chain Complex Induces Apoptosis by a Mitochondria-Targeted Fluorescent Organic Arsenical in vitro and in vivo.
ChemMedChem ( IF 3.6 ) Pub Date : 2020-02-26 , DOI: 10.1002/cmdc.201900686
Yu-Jiao Liu ₁ , Xiao-Yang Fan ₁ , Dong-Dong Zhang ₂ , Yin-Zheng Xia ₁ , Yan-Jun Hu ₃ , Feng-Lei Jiang ₁ , Fu-Ling Zhou ₂ , Yi Liu _{1,

3,

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Affiliation

Based on the potential therapeutic value in targeting mitochondria and the fluorophore tracing ability, a fluorescent mitochondria-targeted organic arsenical PDT-PAO-F16 was fabricated, which not only visualized the cellular distribution, but also exerted anti-cancer activity in vitro and in vivo via targeting pyruvate dehydrogenase complex (PDHC) and respiratory chain complexes in mitochondria. In details, PDT-PAO-F16 mainly accumulated into mitochondria within hours and suppressed the activity of PDHC resulting in the inhibition of ATP synthesis and thermogenesis disorder. Moreover, the suppression of respiratory chain complex I and IV accelerated the mitochondrial dysfunction leading to caspase family-dependent apoptosis. In vivo, the acute promyelocytic leukemia was greatly alleviated in the PDT-PAO-F16 treated group in APL mice model. Our results demonstrated the organic arsenical precursor with fluorescence imaging and target-anticancer efficacy is a promising anticancer drug.

中文翻译：

丙酮酸脱氢酶复合物和呼吸链复合物的双重抑制在体外和体内通过线粒体靶向的荧光有机砷诱导细胞凋亡。

基于靶向线粒体的潜在治疗价值和荧光团的追踪能力，制备了靶向荧光线粒体的有机砷PDT-PAO-F16，它不仅可视化细胞分布，而且在体内外均具有抗癌活性。通过靶向线粒体中的丙酮酸脱氢酶复合物（PDHC）和呼吸链复合物。详细地，PDT-PAO-F16主要在数小时内积累到线粒体中，并且抑制PDHC的活性，从而抑制了ATP合成和生热障碍。此外，抑制呼吸链复合体I和IV加速了线粒体功能障碍，导致caspase家族依赖性细胞凋亡。在体内，在APL小鼠模型中，PDT-PAO-F16治疗组的急性早幼粒细胞白血病得到极大缓解。

更新日期：2020-02-26

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