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Acute Leukemias

(+)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

Leukemia volume 26, pages 451–460 (2012)Cite this article

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.

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Acknowledgements

We are grateful to AB Garcia and DA Gallo for technical assistance in flow cytometry and to CL Silva and LL Alves for handling of transgenic mice. RSAL, PSS, BAASL, ARLA and FPR received financial support from Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP); HLGT and CRP from Coordenação de Aperfeiçoamento de pessoal de nível superior (CAPES). This work was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq—grant # 573754/2008-0) and Fundação de Apoio à Pesquisa do Estado de São Paulo (FAPESP—grant # 1998/14247-6).

Author contributions

GASS designed and performed research, analyzed data and wrote the paper. RSAL performed research and analyzed data of the ‘in vivo experiments’. BAAS-L performed research of the ‘in vivo experiments’. SAU, PPP and HT contributed vital new reagents or analytical tools and discussed data. CC and EMR designed experiments and wrote the paper. All other co-authors performed experiments and analyzed data.

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Authors and Affiliations

  1. 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

    G A S dos Santos, R S Abreu e Lima, A S G Lima, P S Scheucher, C H Thomé, H L Gimenes-Teixeira, B A A Santana-Lemos, A R Lucena-Araujo, R P Falcão & E M Rego

  2. Department of Physics and Chemistry, Pharmaceutical Sciences Faculty of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil

    G A S dos Santos, C R Pestana, F P Rodrigues & C Curti

  3. Department of Internal Medicine, American University of Beirut, Beirut, Lebanon

    R Nasr

  4. CNRS Unité Mixte de Recherche (UMR) 7151, Laboratoire Associé au Comité de Paris de la Ligue contre le Cancer, Paris, France

    R Nasr & H de Thé

  5. Department of Clinical, Toxicological and Bromatological Analysis, Pharmaceutical Sciences Faculty of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil

    S A Uyemura

  6. Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA

    P P Pandolfi

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Correspondence to E M Rego.

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dos Santos, G., Abreu e Lima, R., Pestana, C. et al. (+)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. Leukemia 26, 451–460 (2012). https://doi.org/10.1038/leu.2011.216

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