Abstract
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.
Keywords:
ROS; apoptosis; lactate dehydrogenase A; metabolism; mitochondria; organic arsenicals.
MeSH terms
-
Animals
-
Arsenicals / chemical synthesis
-
Arsenicals / chemistry
-
Arsenicals / pharmacology*
-
Cell Death / drug effects
-
Cell Line, Tumor
-
Cell Proliferation / drug effects
-
Cell Respiration / drug effects
-
Disease Progression*
-
Female
-
Glutathione / metabolism
-
Humans
-
Ki-67 Antigen / metabolism
-
Lactate Dehydrogenase 5 / antagonists & inhibitors
-
Lactate Dehydrogenase 5 / metabolism*
-
Mice, Nude
-
Mitochondria / drug effects
-
Mitochondria / metabolism
-
Mitochondria / ultrastructure
-
Neoplasms / metabolism*
-
Neoplasms / pathology*
-
Organic Chemicals / chemical synthesis
-
Organic Chemicals / chemistry
-
Organic Chemicals / pharmacology*
-
Oxygen Consumption / drug effects
-
Pyruvate Dehydrogenase Complex / metabolism
-
Rats, Wistar
-
Reactive Oxygen Species / metabolism
-
Thioredoxins / metabolism
-
Xenograft Model Antitumor Assays
Substances
-
Arsenicals
-
Ki-67 Antigen
-
Organic Chemicals
-
Pyruvate Dehydrogenase Complex
-
Reactive Oxygen Species
-
Thioredoxins
-
Lactate Dehydrogenase 5
-
Glutathione