title: (+)α-Tocopheryl succinate inhibits the mitochondrial respiratory chain complex I and is as effective as arsenic trioxide or ATRA against acute promyelocytic leukemia in vivo.
abstract: The vitamin E derivative (+)α-tocopheryl succinate (α-TOS) exerts pro-apoptotic effects in a wide range of tumors and is well tolerated by normal tissues. Previous studies point to a mitochondrial involvement in the action mechanism; however, the early steps have not been fully elucidated. In a model of acute promyelocytic leukemia (APL) derived from hCG-PML-RARα transgenic mice, we demonstrated that α-TOS is as effective as arsenic trioxide or all-trans retinoic acid, the current gold standards of therapy. We also demonstrated that α-TOS induces an early dissipation of the mitochondrial membrane potential in APL cells and studies with isolated mitochondria revealed that this action may result from the inhibition of mitochondrial respiratory chain complex I. Moreover, α-TOS promoted accumulation of reactive oxygen species hours before mitochondrial cytochrome c release and caspases activation. Therefore, an in vivo antileukemic action and a novel mitochondrial target were revealed for α-TOS, as well as mitochondrial respiratory complex I was highlighted as potential target for anticancer therapy.
authors.affiliation: Hematology Division, Department of Internal Medicine, National Institute of Science and Technology on Cell Based Therapy, Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
authors.forename: G A S
authors.initials: GA
authors.lastname: dos Santos
authors.forename: R S
authors.initials: RS
authors.lastname: Abreu e Lima
authors.forename: C R
authors.initials: CR
authors.lastname: Pestana
authors.forename: A S G
authors.initials: AS
authors.lastname: Lima
authors.forename: P S
authors.initials: PS
authors.lastname: Scheucher
authors.forename: C H
authors.initials: CH
authors.lastname: Thomé
authors.forename: H L
authors.initials: HL
authors.lastname: Gimenes-Teixeira
authors.forename: B A A
authors.initials: BA
authors.lastname: Santana-Lemos
authors.forename: A R
authors.initials: AR
authors.lastname: Lucena-Araujo
authors.forename: F P
authors.initials: FP
authors.lastname: Rodrigues
authors.forename: R
authors.initials: R
authors.lastname: Nasr
authors.forename: S A
authors.initials: SA
authors.lastname: Uyemura
authors.forename: R P
authors.initials: RP
authors.lastname: Falcão
authors.forename: H
authors.initials: H
authors.lastname: de Thé
authors.forename: P P
authors.initials: PP
authors.lastname: Pandolfi
authors.forename: C
authors.initials: C
authors.lastname: Curti
authors.forename: E M
authors.initials: EM
authors.lastname: Rego
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000627:therapeutic use*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D004195:Disease Models, Animal; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors*; D042963:Electron Transport Complex II / Q000037:antagonists & inhibitors; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000401:mortality; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D010087:Oxides / Q000627:therapeutic use*; D055550:Protein Stability / Q000187:drug effects; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D014185:Transplantation, Isogeneic; D014212:Tretinoin / Q000627:therapeutic use*; D024502:alpha-Tocopherol / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D001152:Arsenicals; D015514:Oncogene Proteins, Fusion; D010087:Oxides; D017382:Reactive Oxygen Species; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D014212:Tretinoin; D045304:Cytochromes c; D042963:Electron Transport Complex II; D020169:Caspases; D042967:Electron Transport Complex I; D024502:alpha-Tocopherol; D000077237:Arsenic Trioxide