Aberrant signaling in T-cell acute lymphoblastic leukemia: biological and therapeutic implications

Cardoso, Bruno; Gírio, Ana; Henriques, Catarina M.; Martins, Leila R.; Santos, Carlos Pereira dos; Silva, A.; Barata, Jorge M. M.

doi:10.1590/s0100-879x2008005000016

Cited by 23 publications

(15 citation statements)

References 54 publications

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“…Acute lymphoblastic leukemia (ALL), the most frequently diagnosed cancer in children ages 0 to 19 years [1], comprises a diverse population of malignant lymphoid progenitors undergoing clonal proliferation at various stages of differentiation [2]. The American Cancer Society estimates that 6,050 people in the United States will be diagnosed with ALL in 2012 [3], and incidence rates of ALL have increased significantly over the past thirty years [1].…”

Section: Introductionmentioning

confidence: 99%

3,3′-Diindolylmethane Induces G1 Arrest and Apoptosis in Human Acute T-Cell Lymphoblastic Leukemia Cells

et al. 2012

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Certain bioactive food components, including indole-3-carbinol (I3C) and 3,3′-diindolylmethane (DIM) from cruciferous vegetables, have been shown to target cellular pathways regulating carcinogenesis. Previously, our laboratory showed that dietary I3C is an effective transplacental chemopreventive agent in a dibenzo[ def,p ]chrysene (DBC)-dependent model of murine T-cell lymphoblastic lymphoma. The primary objective of the present study was to extend our chemoprevention studies in mice to an analogous human neoplasm in cell culture. Therefore, we tested the hypothesis that I3C or DIM may be chemotherapeutic in human T-cell acute lymphoblastic leukemia (T-ALL) cells. Treatment of the T-ALL cell lines CCRF-CEM, CCRF-HSB2, SUP-T1 and Jurkat with DIM in vitro significantly reduced cell proliferation and viability at concentrations 8- to 25-fold lower than the parent compound I3C. DIM (7.5 µM) arrested CEM and HSB2 cells at the G 1 phase of the cell cycle and 15 µM DIM significantly increased the percentage of apoptotic cells in all T-ALL lines. In CEM cells, DIM reduced protein expression of cyclin dependent kinases 4 and 6 (CDK4, CDK6) and D-type cyclin 3 (CCND3); DIM also significantly altered expression of eight transcripts related to human apoptosis ( BCL2L10 , CD40LG , HRK , TNF , TNFRSF1A , TNFRSF25 , TNFSF8 , TRAF4 ). Similar anticancer effects of DIM were observed in vivo . Dietary exposure to 100 ppm DIM significantly decreased the rate of growth of human CEM xenografts in immunodeficient SCID mice, reduced final tumor size by 44% and increased the apoptotic index compared to control-fed mice. Taken together, our results demonstrate a potential for therapeutic application of DIM in T-ALL.

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Section: Introductionmentioning

confidence: 99%

3,3′-Diindolylmethane Induces G1 Arrest and Apoptosis in Human Acute T-Cell Lymphoblastic Leukemia Cells

et al. 2012

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“…Nuclear factor κB (NF-κB) plays a critical role in many biological processes, including cell cycle progression, apoptosis, oncogenesis, inflammation, and various autoimmune diseases [11,12] . Abnormal constitutive NF-κB activation is widely seen in a number of solid tumors and in diverse types of hematopoietic malignancies, such as CML [13] , AML [14] , lymphoma [15,16] , and acute lymphoblastic leukemia (ALL) [17][18][19] . In particular, constitutively activated NF-κB is found selectively in leukemia stem cells and not in normal hematopoietic stem cells [20] .…”

Section: Introductionmentioning

confidence: 99%

Triptolide inhibits the proliferation of cells from lymphocytic leukemic cell lines in association with downregulation of NF-κB activity and miR-16-1*

Meng

Zhu

et al. 2011

Acta Pharmacol Sin

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Aim: To examine the effects of triptolide (TPL) on T-cell leukemia cells and identify their underlying mechanisms. Methods: The cytotoxicity of TPL was assessed by MTT assay. Cell apoptosis was determined using annexin V and DAPI staining and analyzed by flow cytometry or fluorescence microscopy. The activation of caspase pathways and the expression of nuclear factor κB (NF-κB) p65 were examined by Western blotting. Differences in microRNA (miRNA) expression in Molt-4 and Jurkat cells before and after TPL treatment were identified using microarrays and real-time RT-PCR, respectively. Results: TPL 20−160 nmol/L treatment potently inhibited cell growth and induced apoptosis in T-cell lymphocytic leukemia cell lines. Molt-4 and Jurkat cells, however, were more sensitive to TPL than L428 and Raji cells. After 24 h of treatment, bortezomib abrogated the growth of Molt-4 and Jurkat cells with an IC 50 of 15.25 and 24.68 nmol/L, respectively. Using Molt-4 cells, we demonstrated that TPL 20−80 nmol/L inhibited the translocation of NF-κB p65 from the cytoplasm to the nucleus and that phosphorylated NF-κB p65 in nuclear extracts was down-regulated in a dose-dependent manner. Similar results were also seen in Jurkat cells but not in L428 cells, as these cells are resistant to TPL and bortezomib (a NF-κB inhibitor). Twenty-three miRNAs were differentially expressed after TPL treatment. Functional analysis revealed that TPL treatment could inhibit expression of miR-16-1* and that transfection of miR-16-1* led to significantly decreased apoptosis induced by TPL. Conclusion: Our in vitro studies suggest that TPL might be an effective therapeutic agent for treatment of T-cell lymphocytic leukemia and that its cytotoxic effects could be associated with inhibition of NF-κB and down-regulation of miR-16-1*.

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“…The RIPK1 ubiquitinating enzyme BIRC3 (cIAP2) gene expression was upregulated in Dex-treated C7 cells (Cluster 5). BIRC3 and RIPK1 are involved in pathways important in regulating GR such as NF-κB [46]. …”

Section: Resultsmentioning

confidence: 99%

“…To investigate whether CM affects GR phosphorylation, thereby mediating sensitivity or resistance in ALL cells [27, 28, 46] total GR protein levels and its phosphoisoforms S211 and S226 were monitored in ALL cells following Dex and Etop treatment (Fig 4, data not shown).…”

Section: Resultsmentioning

confidence: 99%

Differential regulation of cell death pathways by the microenvironment correlates with chemoresistance and survival in leukaemia

et al. 2017

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Glucocorticoids (GCs) and topoisomerase II inhibitors are used to treat acute lymphoblastic leukaemia (ALL) as they induce death in lymphoid cells through the glucocorticoid receptor (GR) and p53 respectively. Mechanisms underlying ALL cell death and the contribution of the bone marrow microenvironment to drug response/resistance remain unclear. The role of the microenvironment and the identification of chemoresistance determinants were studied by transcriptomic analysis in ALL cells treated with Dexamethasone (Dex), and Etoposide (Etop) grown in the presence or absence of bone marrow conditioned media (CM). The necroptotic (RIPK1) and the apoptotic (caspase-8/3) markers were downregulated by CM, whereas the inhibitory effects of chemotherapy on the autophagy marker Beclin-1 (BECN1) were reduced suggesting CM exerts cytoprotective effects. GCs upregulated the RIPK1 ubiquitinating factor BIRC3 (cIAP2), in GC-sensitive (CEM-C7-14) but not in resistant (CEM-C1-15) cells. In addition, CM selectively affected GR phosphorylation in a site and cell-specific manner. GR is recruited to RIPK1, BECN1 and BIRC3 promoters in the sensitive but not in the resistant cells with phosphorylated GR forms being generally less recruited in the presence of hormone. FACS analysis and caspase-8 assays demonstrated that CM promoted a pro-survival trend. High molecular weight proteins reacting with the RIPK1 antibody were modified upon incubation with the BIRC3 inhibitor AT406 in CEM-C7-14 cells suggesting that they represent ubiquitinated forms of RIPK1. Our data suggest that there is a correlation between microenvironment-induced ALL proliferation and altered response to chemotherapy.

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Aberrant signaling in T-cell acute lymphoblastic leukemia: biological and therapeutic implications

Cited by 23 publications

References 54 publications

3,3′-Diindolylmethane Induces G1 Arrest and Apoptosis in Human Acute T-Cell Lymphoblastic Leukemia Cells

3,3′-Diindolylmethane Induces G1 Arrest and Apoptosis in Human Acute T-Cell Lymphoblastic Leukemia Cells

Triptolide inhibits the proliferation of cells from lymphocytic leukemic cell lines in association with downregulation of NF-κB activity and miR-16-1*

Differential regulation of cell death pathways by the microenvironment correlates with chemoresistance and survival in leukaemia

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