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 inâ vitro and inâ 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.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Arsenicals/pharmacology , Electron Transport/drug effects , Enzyme Inhibitors/pharmacology , Leukemia, Promyelocytic, Acute/drug therapy , Pyruvate Dehydrogenase Complex/antagonists & inhibitors , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Arsenicals/chemical synthesis , Arsenicals/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Female , Humans , 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/metabolism , Reactive Oxygen Species/metabolismABSTRACT
Based on the potential therapeutic value in targeting metabolism for the treatment of cancer, an organic arsenical PDT-BIPA was fabricated, which exerted selective anti-cancer activity in vitro and in vivo via targeting lactate dehydrogenase A (LDHA) to remodel the metabolic pathway. In details, the precursor PDT-BIPA directly inhibited the function of LDHA and converted the glycolysis to oxidative phosphorylation causing ROS burst and mitochondrial dysfunction. PDT-BIPA also altered several gene expression, such as HIF-1α and C-myc, to support the metabolic remodeling. All these changes lead to caspase family-dependent cell apoptosis in vivo and in vitro without obvious side effect. Our results provided this organic arsenical precursor as a promising anticancer candidate and suggested metabolism as a target for cancer therapies.
Subject(s)
Arsenicals/pharmacology , Disease Progression , Lactate Dehydrogenase 5/metabolism , Neoplasms/metabolism , Neoplasms/pathology , Organic Chemicals/pharmacology , Animals , Arsenicals/chemical synthesis , Arsenicals/chemistry , Cell Death/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Respiration/drug effects , Female , Glutathione/metabolism , Humans , Ki-67 Antigen/metabolism , Lactate Dehydrogenase 5/antagonists & inhibitors , Mice, Nude , Mitochondria/drug effects , Mitochondria/metabolism , Mitochondria/ultrastructure , Organic Chemicals/chemical synthesis , Organic Chemicals/chemistry , Oxygen Consumption/drug effects , Pyruvate Dehydrogenase Complex/metabolism , Rats, Wistar , Reactive Oxygen Species/metabolism , Thioredoxins/metabolism , Xenograft Model Antitumor AssaysABSTRACT
Considering the vital role of mitochondria in the anti-cancer mechanism of organic arsenical, the mitochondria-targeted precursor PDT-PAO-TPP was designed and synthesized. PDT-PAO-TPP, as a delocalization lipophilic cation (DLCs) which mainly accumulated in mitochondria, contributed to improve anti-cancer efficacy and selectivity towards NB4 cells. In detail, PDT-PAO-TPP inhibited the activity of PDHC resulting in the suppression of ATP synthesis and thermogenesis disorder. Additionally, the inhibition of respiratory chain complex I and IV by short-time incubation of PDT-PAO-TPP also accelerated the respiration dysfunction and continuous generation of ROS. These results led to the release of cytochrome c and activation of caspase family-dependent apoptosis. Different from the mechanism of PDT-PAO in HL-60 cells, it mainly induced the mitochondrial metabolic disturbance resulting in the intrinsic apoptosis via inhibiting the activity of PDHC in NB4 cells, which also implied that the efficacy exertion of organic arsenical was a complex process involved in many aspects of cellular function. This study systematically clarifies the anti-cancer mechanism of mitochondria-targeted organic arsenical PDT-PAO-TPP and confirms the new target PDHC of organic arsenicals, which further supports the organic arsenical as a promising anticancer drug.
