Determination of the in vivo effects of prednisone on Bcl-2 family protein expression in childhood acute lymphoblastic leukemia

Casale, Fiorina; Addeo, Raffaele; D’Angelo, Velia; Indolfi, Paolo; Poggi, Vincenzo; Morgera, C.; Crisci, Stefania; Tullio, Maria Teresa Di

doi:10.3892/ijo.22.1.123

Cited by 21 publications

(23 citation statements)

References 16 publications

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“…Furthermore, overexpression of antiapoptotic Bcl-2 family members attenuated GC-induced cell death both in mouse thymocytes 69 and human ALL 47,70 and myeloma 71 cell lines. Since induction of proapoptotic 33,72 and repression of antiapoptotic 34,73 Bcl-2 family proteins has been observed in GC-treated cells, transcriptional deregulation of the Bcl-2 rheostat may be an essential principle for GCinduced apoptosis in many systems. However, as discussed below and depicted in Figure 3, the situation may become more complex in the presence of overexpressed antiapoptotic Bcl-2 family members or other prosurvival genes.…”

Section: Gc-induced Apoptosis As Results Of Direct Regulation Of Deathmentioning

confidence: 99%

“…Regarding the latter, expression of Bcl-2 family members was investigated in numerous studies with somewhat conflicting outcomes. For instance, some investigators suggested that Bcl-XL 73 or the Bax-a:Bcl-2 ratio 107 might play a role in the protection of leukemic cells from GC-induced apoptosis, but one report found no alterations in Bax and Bcl-2 expression during in vivo chemotherapy, 108 and another concluded that neither Bcl-2 nor Bcl-XL, Mcl-1, Bax, Bad or Bak had prognostic significance in such children at diagnosis. 109 Interestingly, Bcl-2 was increased in relapsed ALL samples, 110 and downregulation of Bcl-2 or Bcl-XL by antisense oligonucleotides lead to sensitization of leukemia or myeloma cell lines, and freshly isolated myeloma cells from patients.…”

Section: 'Downstream Mechanisms' Interfering With Death or Activatingmentioning

confidence: 99%

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Glucocorticoid-induced apoptosis and glucocorticoid resistance: molecular mechanisms and clinical relevance

et al. 2004

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The ability of glucocorticoids (GC) to efficiently kill lymphoid cells has led to their inclusion in essentially all chemotherapy protocols for lymphoid malignancies. This review summarizes recent findings related to the molecular basis of GC-induced apoptosis and GC resistance, and discusses their potential clinical implications. Accumulating evidence suggests that GC may induce cell death via different pathways resulting in apoptotic or necrotic morphologies, depending on the availability/responsiveness of the apoptotic machinery. The former might result from regulation of typical apoptosis genes such as members of the Bcl-2 family, the latter from detrimental GC effects on essential cellular functions possibly perpetuated by GC receptor (GR) autoinduction. Although other possibilities exist, GC resistance might frequently result from defective GR expression, perhaps the most efficient means to target multiple antileukemic GC effects. Numerous novel drug combinations are currently being tested to prevent resistance and improve GC efficacy in the therapy of lymphoid malignancies.

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Section: Gc-induced Apoptosis As Results Of Direct Regulation Of Deathmentioning

confidence: 99%

Section: 'Downstream Mechanisms' Interfering With Death or Activatingmentioning

confidence: 99%

Glucocorticoid-induced apoptosis and glucocorticoid resistance: molecular mechanisms and clinical relevance

et al. 2004

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“…Studies in human ALL cell lines showed that members of the anti-apoptotic Bcl-2 protein family were able to diminish Gc-mediated apoptosis in human ALL cell lines when overexpressed (Brunet et al 1998, Hartmann et al 1999. It has become evident that Gc-mediated apoptosis includes the upregulation of pro-apoptotic (Han et al 2001 and/or downregulation of anti-apoptotic genes (Chauhan et al 2002, Casale et al 2003 and this would therefore suggest that altering the expression levels of proteins involved in the Bcl-2 rheostat provides a mechanism for explaining Gc-mediated apoptosis .…”

Section: Resistance To Gc-induced Apoptosis In Lymphoblastic Leukaemiamentioning

confidence: 99%

“…Gcs can activate cell death through induction of pro-apoptotic members of the Bcl-2 family, such as Bim, Bid and Bad (Han et al 2001, Lu et al 2007) and/or repression of anti-apoptotic members, such as Bcl-2, Mcl-1 and Bcl-xL, (Rogatsky et al 1999, Casale et al 2003, Chauhan et al 2003, Lu et al 2007). Gc-induced apoptosis is also compromised in thymocytes from mice deficient in pro-apoptotic proteins Apaf1 (Yoshida et al 1998) or caspase 9 (Kuida et al 1998).…”

Section: Effects Of Gcs On Apoptosismentioning

confidence: 99%

Glucocorticoid receptor-mediated apoptosis: mechanisms of resistance in cancer cells

Schlossmacher

Stevens²,

White

2011

Journal of Endocrinology

136

110

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Glucocorticoids (Gcs) are commonly used to treat patients suffering from a wide range of cancers. Their main therapeutic role is based on Gc receptor (GR)-mediated mechanisms that trigger cell death but this varies depending on the cancer type. This review aims to provide an overview of the mechanisms of Gc-induced cell death and more importantly the changes in GR that lead to resistance to Gc treatment in cancer. The three main cancer types, which are susceptible to Gc resistance and therefore loss of Gc-induced apoptotic effects, are acute lymphoblastic leukaemia, osteosarcoma and small-cell lung carcinoma. A common theme is the loss of GR function and/or a downregulation of GR expression which leads to failure of the cell death-inducing effects of Gcs. Loss of GR function is attributed to mutations in the GR gene, and in some cases a dominant-negative effect on any functional GR still present. The downregulation of GR expression can be due to decreased GR promoter activation, increased GR promoter methylation or increased expression of alternative splice isoforms of GR that have decreased transcriptional activity. Understanding the mechanisms behind Gc-triggered apoptosis and the resistance to it in these cancer types will help in further refining treatment regimens for patients and will decrease the chance of relapse caused by Gc-resistant cancer phenotypes.

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“…No association between Bcl-2 expression and other phenotypic markers was identified. Although prior studies using Western blot analysis and gene expression profiling have reported decreased Bcl-2 expression in ALL following glucocorticoid therapy (24,25), the current study demonstrated over-expression of Bcl-2 in the few specimens obtained following steroid-containing induction therapy. As previously reported, Bcl-2 over-expression was also identified at relapse of B-LL (15,21,22) …”

Section: Discussionmentioning

confidence: 73%

ZAP‐70 and Bcl‐2 expression in B lymphoblastic leukemia cells and hematogones

Craig

Monaghan

Surti

et al. 2011

Cytometry Part B Clinical

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Background: Flow cytometric immunophenotyping has an established role in the diagnosis and monitoring of B-lymphoblastic leukemia (B-LL). However, the search continues for an optimal reagent set that can identify leukemic blasts with specificity, reproducibility, and sensitivity, at any point during the course of the disease and in every specimen type.Methods: This study evaluated the diagnostic utility of detecting the intracytoplasmic antigens zetaassociated protein (ZAP-70) and Bcl-2 in the distinction between the leukemic blasts of B-LL and hematogones.Results: In comparison with hematogones in reference specimens, significantly higher levels of Bcl-2 were identified in 21 of 23 (91%) B-LL. In particular, Bcl-2 expression was consistently higher in leukemic blasts with bright intensity CD10 expression than the equivalent most immature (CD10 bright intensity) hematogones. As previously reported, Bcl-2 expression was lower in B-LL with BCR-ABL1 gene rearrangement, but the fluorescence intensity of this group of specimens was still significantly higher than that seen for hematogones. In contrast, ZAP-70 was expressed at significantly higher levels in only 7 of 23 (30%) B-LL and demonstrated other findings that might limit clinical utility, including differences in the level of ZAP-70 expression during therapy and between blasts in the peripheral blood and bone marrow.Conclusions: Bcl-2 over-expression provides a useful tool for the distinction between B-LL and hematogones. In contrast, although further optimization of the ZAP-70 assay might increase the sensitivity of detection, over-expression of ZAP-70 was identified in only a minority of B-LL. V C 2011 International Clinical Cytometry Society

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Determination of the in vivo effects of prednisone on Bcl-2 family protein expression in childhood acute lymphoblastic leukemia

Cited by 21 publications

References 16 publications

Glucocorticoid-induced apoptosis and glucocorticoid resistance: molecular mechanisms and clinical relevance

Glucocorticoid-induced apoptosis and glucocorticoid resistance: molecular mechanisms and clinical relevance

Glucocorticoid receptor-mediated apoptosis: mechanisms of resistance in cancer cells

ZAP‐70 and Bcl‐2 expression in B lymphoblastic leukemia cells and hematogones

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