(+)alpha-Tocopheryl succinate inhibits the mitochondrial respiratory chain complex I and is as effective as arsenic trioxide or ATRA against acute promyelocytic leukemia in vivo

Autor(es):Mostrar menos -

dos Santos, G. A. S. ^{[1, 2]} ; Abreu e Lima, R. S. ^[1] ; Pestana, C. R. ^[2] ; Lima, A. S. G. ^[1] ; Scheucher, P. S. ^[1] ; Thome, C. H. ^[1] ; Gimenes-Teixeira, H. L. ^[1] ; Santana-Lemos, B. A. A. ^[1] ; Lucena-Araujo, A. R. ^[1] ; Rodrigues, F. P. ^[2] ; Nasr, R. ^{[3, 4]} ; Uyemura, S. A. ^[5] ; Falcao, R. P. ^[1] ; de The, H. ^[4] ; Pandolfi, P. P. ^[6] ; Curti, C. ^[2] ; Rego, E. M. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Div Hematol, Natl Inst Sci & Technol Cell Based Therapy, Dept Internal Med, Med Sch Ribeirao Preto, BR-14049 Ribeirao Preto - Brazil

^[2] Univ Sao Paulo, Dept Phys & Chem, Pharmaceut Sci Fac Ribeirao Preto, BR-14049 Ribeirao Preto - Brazil

^[3] Amer Univ Beirut, Dept Internal Med, Beirut - Lebanon

^[4] Lab Associe Com Paris Ligue Canc, CNRS, UMR 7151, Paris - France

^[5] Univ Sao Paulo, Dept Clin Toxicol & Bromatol Anal, Pharmaceut Sci Fac Ribeirao Preto, BR-14049 Ribeirao Preto - Brazil

^[6] Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 - USA

• Tipo de documento: Artigo Científico
• Fonte: LEUKEMIA; v. 26, n. 3, p. 451-460, MAR 2012.
• Citações Web of Science: 36

Resumo

The vitamin E derivative (+)alpha-tocopheryl succinate (alpha-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-RAR alpha transgenic mice, we demonstrated that alpha-TOS is as effective as arsenic trioxide or all-trans retinoic acid, the current gold standards of therapy. We also demonstrated that alpha-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, alpha-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 alpha-TOS, as well as mitochondrial respiratory complex I was highlighted as potential target for anticancer therapy. Leukemia (2012) 26, 451-460; doi:10.1038/leu.2011.216; published online 26 August 2011 (AU)

• Processo FAPESP: 98/14247-6 - Center for Research on Cell-Based Therapy
• Beneficiário: Marco Antonio Zago
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs