title: The heme precursor 5-aminolevulinic acid disrupts the Warburg effect in tumor cells and induces caspase-dependent apoptosis.
abstract: Our previous study demonstrated that 5-aminolevulinic acid (ALA) administered to mice stimulates oxidative phosphorylation by upregulation of the mitochondrial respiratory chain complex IV enzyme cytochrome c oxidase (COX). The present study investigated whether ALA disrupts the Warburg effect, which represents a shift in ATP generation from oxidative phosphorylation to glycolysis, protecting tumor cells against oxidative stress-mediated apoptosis. The human lung carcinoma cell line A549 exposed to ALA exhibited enhanced oxidative phosphorylation, which was indicated by an increase in COX protein expression and oxygen consumption. Furthermore, ALA suppressed glycolysis-mediated acidosis. This normalization of the ATP metabolic pathways significantly increased the generation of superoxide anion radical (O2•-) and the functional expression of active caspase-3, leading to caspase-dependent apoptosis. These data demonstrate that ALA inhibits the Warburg effect and induces cancer cell death. Use of this endogenous compound might constitute a novel approach to cancer therapy.
authors.affiliation: Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Kanagawa 226‑8501, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Sugiyama
authors.affiliation: Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Kanagawa 226‑8501, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Hagiya
authors.affiliation: SBI Pharmaceuticals Co., Ltd., Tokyo 106-6020, Japan.
authors.forename: Motowo
authors.initials: M
authors.lastname: Nakajima
authors.affiliation: SBI Pharmaceuticals Co., Ltd., Tokyo 106-6020, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ishizuka
authors.affiliation: SBI Pharmaceuticals Co., Ltd., Tokyo 106-6020, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Kanagawa 226‑8501, Japan.
authors.forename: Shun-Ichiro
authors.initials: S
authors.lastname: Ogura
mesh_terms: D000622:Aminolevulinic Acid / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006019:Glycolysis / Q000187:drug effects*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D010085:Oxidative Phosphorylation / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D013481:Superoxides; D000622:Aminolevulinic Acid; C505407:CASP3 protein, human; D053148:Caspase 3