1. (+)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
- Author
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Antonio R. Lucena-Araujo, G.A. dos Santos, Anderson Lima, Carlos Curti, H. L. Gimenes-Teixeira, Pier Paolo Pandolfi, Fernando P. Rodrigues, Barbara A. Santana-Lemos, R. S. Abreu e Lima, Cezar R. Pestana, Priscila Santos Scheucher, E.M. Rego, Sérgio Akira Uyemura, Rihab Nasr, Carolina Hassibe Thomé, and Roberto Passetto Falcão
- Subjects
Acute promyelocytic leukemia ,Cancer Research ,Oncogene Proteins, Fusion ,alpha-Tocopherol ,Retinoic acid ,Antineoplastic Agents ,Apoptosis ,Mice, Transgenic ,Tretinoin ,Pharmacology ,Antioxidants ,Arsenicals ,Mice ,chemistry.chemical_compound ,Arsenic Trioxide ,Leukemia, Promyelocytic, Acute ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Mitochondrial respiratory chain complex I ,Arsenic trioxide ,Caspase ,Membrane Potential, Mitochondrial ,chemistry.chemical_classification ,Reactive oxygen species ,Electron Transport Complex I ,biology ,Protein Stability ,Electron Transport Complex II ,Cytochromes c ,Oxides ,Hematology ,medicine.disease ,Mitochondria ,Rats ,Transplantation ,Disease Models, Animal ,Transplantation, Isogeneic ,Leukemia ,Oncology ,chemistry ,Caspases ,Neoplastic Stem Cells ,biology.protein ,Reactive Oxygen Species - 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.
- Published
- 2011
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