Hamilton Luiz Gimenes Teixeira

Succinate of α tocopherol (VES) is a derivative of vitamin E with well-known antioxidant and pro-apoptotic activities. It has been demonstrated that VES induces apoptosis in different solid tumor cells and preliminary clinical data suggest that the use of vitamin E in association to first-line chemotherapy may improve the efficacy of therapy, without significant adverse effects. About one third of the patients with acute promyelocytic leukemia (APL) relapse after treatment with all trans retinoic acid (ATRA) and many of them present resistance to further treatment with ATRA. Therefore, the development of new strategies effective to the treatment of APL would be relevant to improve survival of ATRA-resistant patients. In order to determine whether VES would induce apoptosis and/or differentiation of APL cells, we treated in vitro NB4 and leukemic cells from 11 patients with APL harboring PML/RARα rearragements with 20, 40, 80 or 120μg/mL of VES or vehicle (DMSO, control) for 3, 6, 12...

Acute promyelocytic leukemia (APL) is characterized by the infiltration of bone marrow (BM) and peripheral blood (PB) by leukemic cells presenting a block of differentiation at the stage of promyelocytes. At the cytogenetic level, APL is associated with the t(15;17) which causes the fusion of two genes: Retinoic Receptor α (RARα) and Promyelocytic Leukemia (PML), on chromosomes 17 and 15, respectively. C/EBPα is a leucine zipper transcription factor essential to normal granulopoiesis. Mutations in C/EBPα gene are detected in 6–10% of Acute Myeloid Leukemia (AML) cases and C/EBPα activity is down-regulated by AML1-ETO fusion protein associated with FAB M2 subtype. We decided to test whether PML-RARα interferes with C/EBPα function, thus contributing to the blockage of differentiation characteristic of APL. We generated mutant mice expressing PML-RARα and haploinsufficient for C/EBPα (PR C/EBPα+/−) by crossing hCG PML-RARα transgenic mice (PR TM) and C/EBPα+/−. Leukemia was not detect...

As2O3 has been successfully been employed in the treatment of patients with acute promyelocytic leukemia (APL), however it is unavailable to most APL patients in Latin America, and the lack of alternative treatments lead to a very poor prognosis of relapsed/ATRA resistant patients. Here we investigate the anti-leukemic effect of alpha tocopherol succinate (VES) (a vitamin E analog with antiproliferative activity against several cancer cell types) which was shown to activate the intrinsic cell death mediators of caspase-9 and -3 by both its strong redox activity and inhibition of protein kinase C (PKC) and target Akt and JNK pathways. We used a syngenic transplantation model of APL: blasts from hCG-PML/RARalpha transgenic mice (TM) were IV injected in irradiated non-transgenic littermates. Massive infiltration of bone marrow (BM), spleen and liver was detected by 21st day post transplant. Recipient mice were treated with: VES (50UI/g/d) (n=15), As2O3 (2.5μg/g/d) (n=15), VES + As2O3 (...

4802 Caffeic acid phenethyl ester (CAPE) is an active phenolic compound present in propolis obtained from honeybee hives. It is reported to present a spectrum of biological activities including antioxidant, anti-inflammatory and antitumoral. The antitumoral activity of CAPE as evaluated by several studies in vitro and in vivo seems to be related to distinct effects like inhibition of angiogenesis, invasion and metastasis and induction of apoptosis or differentiation of cancer cells. In the scenario of AML the demonstration of CAPE-induced apoptosis or cellular differentiation is restricted to the HL-60 cell line. Our aim was to evaluate the effects of CAPE treatment on primary AML samples as well as APL cell lines NB4 and NB4-R2 (a cell resistant to ATRA-induced differentiation) and on AML cell line Kasumi-1 (representative of core binding factor leukemia with AML1-ETO rearrangement). Proliferation and viability was evaluated by cell count with tripan blue in Neubauer chamber at fix...

Background CD56 expression has been associated with a poor prognosis in lymphoid neoplasms, including T-cell acute lymphoblastic leukemia (T-ALL). MicroRNAs (miRNAs) play an important role in lymphoid differentiation, and aberrant miRNA expression has been associated with treatment outcome in lymphoid malignancies. Here, we evaluated miRNA expression profiles in normal thymocytes, mature T-cells, and T-ALL samples with and without CD56 expression and correlated microRNA expression with treatment outcome. Methods The gene expression profile of 164 miRNAs were compared for T-ALL/CD56+ (n=12) and T-ALL/CD56- (n=36) patients by Real-Time Quantitative PCR. Based on this analysis, we decided to evaluate miR-221 and miR-374 expression in individual leukemic and normal samples. Results miR-221 and miR-374 were expressed at significantly higher levels in T-ALL/CD56+ than in T-ALL/CD56- cells and in leukemic blasts compared with normal thymocytes and peripheral blood (PB) T-cells. Age at diag...

We analyzed the effect of (+)alpha-tocopheryl succinate (alpha-TOS) alone or associated with arsenic trioxide (ATO) or all-trans retinoid acid (ATRA) in acute promyelocytic leukemia (APL). alpha-TOS-induced apoptosis in APL clinical samples and in ATRA-sensitive (NB4) and ATRA-resistant (NB4-R2) APL cell lines. The effective dose 50% (ED-50) was calculated to be 71 and 58muM, for NB4 and NB4-R2, respectively. alpha-TOS neither induced nor modified ATRA-induced differentiation of APL cells, and did not affect the proliferation and differentiation of normal CD34(+) hematopoietic progenitors in methylcellulose assays. alpha-TOS exerted a moderate antagonistic effect to ATO-induced apoptosis when treatment was done simultaneously but when alpha-TOS was added 24h after ATO, an additive effect was observed. Our results support the concept of alpha-TOS as an anti-leukemic compound which spares normal hematopoiesis.