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

Yu-Jiao Liu; Xiao-Yang Fan; Dong-Dong Zhang; Yin-Zheng Xia; Yan-Jun Hu; Feng-Lei Jiang; Fu-Ling Zhou; Yi Liu

doi:10.1002/cmdc.201900686

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. 2020 Mar 18;15(6):552-558. doi: 10.1002/cmdc.201900686. Epub 2020 Feb 26.

Authors

Yu-Jiao Liu¹, Xiao-Yang Fan¹, Dong-Dong Zhang², Yin-Zheng Xia¹, Yan-Jun Hu³, Feng-Lei Jiang¹, Fu-Ling Zhou², Yi Liu^{1

3

4}

Affiliations

¹ Department of Chemistry, Wuhan University, Wuhan, 430072, China.
² Department of Haematology, Zhongnan Hospital, Wuhan University, Wuhan, 430071, China.
³ College of Chemistry and Materials Science, Nanning Normal University, Nanning, 530001, China.
⁴ School of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan, 430081, China.

PMID: 32101363
DOI: 10.1002/cmdc.201900686

Abstract

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.

Keywords: Arsenic; PDHC; apoptosis; leukemia; mitochondria.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects*
Arsenicals / chemical synthesis
Arsenicals / chemistry
Arsenicals / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Electron Transport / drug effects*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Female
Humans
Leukemia, Promyelocytic, Acute / drug therapy*
Leukemia, Promyelocytic, Acute / metabolism
Leukemia, Promyelocytic, Acute / pathology
Mice
Mice, Inbred C57BL
Mitochondria / drug effects
Mitochondria / metabolism
Molecular Structure
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / metabolism
Neoplasms, Experimental / pathology
Pyruvate Dehydrogenase Complex / antagonists & inhibitors*
Pyruvate Dehydrogenase Complex / metabolism
Reactive Oxygen Species / metabolism

Substances

Antineoplastic Agents
Arsenicals
Enzyme Inhibitors
Pyruvate Dehydrogenase Complex
Reactive Oxygen Species