RESUMO
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.
Assuntos
Arsenicais/uso terapêutico , Complexo I de Transporte de Elétrons/antagonistas & inibidores , Leucemia Promielocítica Aguda/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Óxidos/uso terapêutico , Tretinoína/uso terapêutico , alfa-Tocoferol/farmacologia , alfa-Tocoferol/uso terapêutico , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Apoptose/efeitos dos fármacos , Trióxido de Arsênio , Caspases/metabolismo , Linhagem Celular Tumoral , Citocromos c/metabolismo , Modelos Animais de Doenças , Complexo II de Transporte de Elétrons/antagonistas & inibidores , Humanos , Leucemia Promielocítica Aguda/mortalidade , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Estabilidade Proteica/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio/metabolismo , Transplante IsogênicoRESUMO
PCR has been used to analyze the distribution of REP (Repetitive Extragenic Palindromic) and ERIC (Enterobacterial Repetitive Intergenic Consensus) sequences (rep-PCR) found within the genome of the bacterium Bacillus thuringiensis, with the purpose to analyze the genetic similarities among 56 subspecies samples and 95 field isolates. The PCR products were analyzed by EB-AGE (ethidium bromide-agarose electrophoresis) and then submitted to banding comparisons, based on the Phyllip software algorithm. When the banding similarities were considered for comparison purposes among all the strains, the phylogenic tree patterns varied according to the rep-PCR primers considered, but, from a broader point of view, the ERIC sequences produced better results, which, together with electron microscopy analysis of the released parasporal bodies and colony morphology characteristics, allowed to detect two possible new subspecies of B. thuringiensis