Bcl-2 expression and glucocorticoid-induced apoptosis of leukemic and lymphoma cells

Smets, L. A.; Berg, van den Arie

doi:10.3109/10428199609051608

Cited by 30 publications

(21 citation statements)

References 45 publications

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“…34 Accordingly, a decrease in the level of mono(ADP-ribose) adducts in GC receptor-associated HSP90 proteins could possibly be a common stress-sensing event and the target process of MIBG action, eg by inhibiting the reassociation of the heat-activated receptor complexes (Figure 7). At minimally toxic doses the antimitochondrial drug rotenone did not reproduce the potentiations by MIBG, but has comparable effects on cellular ATP content in these 17 and other cell lines. 14 This observation and the failing potentiation by MIBG to cold argue against an important role of antimitochondrial effects of MIBG in the potentiation of Bcl-2-negative S49 variants, contrary to previous findings in Bcl-2 overexpressing lymphoma cells.…”

Section: Discussionmentioning

confidence: 82%

“…Conceptually, cross-resistance of H.2 cells could be due to autocrine production of growth/survival factors, which can rescue several cells of T origin from apoptosis by DEX and low serum. [15][16][17] Because interleukins have been reported to protect T cells by maintaining or upregulating Bcl-2 levels, 15,32 the failure to rescue S49 cells from DEX and low serum by exogenous interleukins, and by inference the H.2 cells by autocrine growth factors, may be attributed to the intrinsically low expression of the bcl-2 gene.…”

Section: Discussionmentioning

confidence: 99%

“…Apoptosis of leukemic cells and normal thymocytes is critically controlled by the expression levels of the genes bcl-2 and bax [12][13][14] and exogenous growth factors and mitogenic stimulation can rescue lymphoid cells from both DEX-mediated and spontaneous apoptosis. [15][16][17] To investigate if the GC receptor is indeed involved in stress-induced apoptosis, we have studied its subcellular distribution and ligand binding capacity in S49 mouse T lymphoma cells, exposed to heat shock, cold shock, low serum concentration or high cell density. In addition, receptor activation was studied in clonal H.2 variants, selected for crossresistance to DEX and stress conditions while remaining sensitive to several other inducers.…”

Section: Introductionmentioning

confidence: 99%

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Involvement of the glucocorticoid receptor in stress-induced apoptosis of leukemic cells

et al. 1998

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Glucocorticoid (GC) hormones induce apoptosis in lymphoid and leukemic cells by binding and activating cytosolic GC receptors. Because physiological stress often causes hormone-free GC receptor activation, we have investigated if stress-induced apoptosis of lymphoid cells is also mediated by the activation of the GC receptor pathway. In S49 T lymphoma cells, heat shock and deprivation of growth factors or nutrients caused nuclear translocation and loss of agonist binding capacity of GC receptors, similar to that in cells incubated with the glucocorticoid dexamethasone (DEX). In variant S49 H.2 cells, cross-resistance to DEX, temperature shocks and growth factor deprivation were associated with a higher threshold for hormone-dependent and -independent receptor activation in situ and with impaired in vitro activation of cytosolic receptors. Cross-resistance to DEX, low serum and heat shock was abrogated, however, by pharmacological sensitization of GC receptor activation with the drug meta-iodobenzylguanidine (MIBG). Sensitive S49 cells and resistant variants did not differ in the expression levels of the apoptosis-regulating genes bax, bad, bcl-X and bcl-2, the status of the p53 gene nor in a different requirement for the growth factors Il-2, IL-4 or IL-9. The results suggest that ligand-independent activation of the GC receptor is a central signalling and controlling event in some forms of stress-induced apoptosis, assigning a novel function to the GC receptor in the regulation of lymphoid and leukemic cell numbers.

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Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Involvement of the glucocorticoid receptor in stress-induced apoptosis of leukemic cells

et al. 1998

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“…However, it can not be excluded that these few patients were resistant due to other, Bcl-2-independent mechanisms, eg by deficiencies in hormone binding and receptor activation. [32][33][34] We and others did not find an independent relationship between Bcl-2 and treatment outcome. 12,13 In addition, the present study indicates no gain in prognostic information by including Bax, Bak, Bcl-x L and Bad.…”

Section: Discussionmentioning

confidence: 92%

True

1999

Leukemia

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We have found that, in addition to Bcl-2 and Bax, the expression levels of apoptosis inducers (Bad, Bak) and inhibitors (Bcl-x L , Mcl-1) were highly variable in blasts from 78 children with newly diagnosed acute lymphoblastic leukemia (ALL). The patients were enrolled in the national study ALL-7 of the Dutch Childhood Leukemia Study Group. In contrast to Bcl-2 that inversely correlated with %S-phase cells and WBC, and was lower in T than in B-lineage ALL, the Bcl-2 family members were not found to be associated with features at presentation. These expression levels were also compared with drug resistance in in vitro MTT (methyl-thiazol-tetrazolium) assays for prednisolone, vincristine and asparaginase in 46 children. Protein expression levels of the Bcl-2 family were not found to correlate with in vitro resistance to the individual drugs or the combined drug resistance profile. In addition, neither peripheral blast reduction after 1 week of prednisone monotherapy nor long-term disease-free interval or survival showed a correlation with protein expression. Our results indicate that the anti-proliferative function of Bcl-2 dominates its anti-apoptotic function in ALL, but neither Bcl-2 nor the Bcl-2 family members gained prognostic information in the risk-adapted protocol ALL-7.

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“…However, these effects are transient in the continuous presence of GC, and Bcl-2 does not prevent cell cycle arrest (Hartmann et al 1999), altogether limiting its potential in a selection process that requires both proliferation and survival. In any case, expression of anti-apoptotic Bcl-2 members is frequent in leukemic cell lines and primary cells from patients prior to, and particularly after combination chemotherapy, and has been associated with resistance to chemotherapeutic drugs and GC (Smets & Van den Berg 1996, Salomons et al 1997.…”

Section: Gc Resistance As Results Of Inhibitory Cross-talk At the Effementioning

confidence: 99%

Resistance to glucocorticoid-induced apoptosis in lymphoblastic leukemia

Kofler¹,

Schmidt²,

Kofler³

et al. 2003

Journal of Endocrinology

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Glucocorticoid (GC) resistance is a phenomenon of major significance in a number of clinical situations, including the therapy of lymphoid malignancies. Resistance may concern all, or just selected, GC effects, it may be absolute or just reflect a state of reduced sensitivity and, clinically relevant, be reversible or irreversible. Numerous molecular mechanisms can be envisaged acting either 'upstream' in the GC-triggered signaling pathway, i.e. at the level of the GC receptor (GR), or 'downstream' at the level of the GC-regulated genes responsible for individual GC effects.In lymphoid malignancies, GCs have anti-leukemic effects through the induction of apoptosis and/or cell cycle arrest. In this condition evidence for only a small number of mechanisms for GC resistance has been provided, mostly at the level of the GR. Herein, we review reports and hypotheses regarding 'upstream' and 'downstream' mechanisms for GC resistance in lymphoblastic leukemia and present an in vitro GC resistance model that might allow identification of resistance mechanisms.

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Bcl-2 expression and glucocorticoid-induced apoptosis of leukemic and lymphoma cells

Cited by 30 publications

References 45 publications

Involvement of the glucocorticoid receptor in stress-induced apoptosis of leukemic cells

Involvement of the glucocorticoid receptor in stress-induced apoptosis of leukemic cells

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Resistance to glucocorticoid-induced apoptosis in lymphoblastic leukemia

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