Recent insights into the mechanism of glucocorticosteroid-induced apoptosis

Distelhorst, Clark W.

doi:10.1038/sj.cdd.4400969

Cited by 265 publications

(192 citation statements)

References 113 publications

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“…8 Although there is some controversy about the role of this transcription factor in cell apoptosis, most data support an NF-kB antiapoptotic action. 28 In addition, it has been shown that cells that are naturally resistant to TNF-induced apoptosis become susceptible when transfected with an expression vector for IkBa, which inactivates NF-kB. 26 Consistent with these findings, we observed that the presence of FP and, to a greater extent, the combined presence of FP and salmeterol reduced the expression of phosphorylated IkBa, which, in turn, leads to an increased IkBa concentration and inhibition of NF-kB activity.…”

Section: Discussionsupporting

confidence: 80%

Synergistic effects of fluticasone propionate and salmeterol on in vitro T-cell activation and apoptosis in asthma

Pace¹,

Gagliardo²,

Melis³

et al. 2004

Journal of Allergy and Clinical Immunology

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Background: In asthma T cells are characterized by an increased activation state and by reduced apoptosis. Objective: Because the clinical efficacy of inhaled corticosteroids combined with long-acting b 2 -agonists has been widely demonstrated in asthma, we studied, in vitro, the effect of fluticasone propionate (FP) and salmeterol alone and in combination on the activation and apoptosis of peripheral blood T cells (PBTs), on the expression of phosphorylated nuclear factor kB inhibitor (IkBa), and on the nuclear translocation of glucocorticoid receptor (GR) in PBTs from asthmatic subjects. Methods: Apoptosis was evaluated on the basis of annexin V binding, whereas the expression of caspases 8 and 3 and phosphorylated IkBa, as well as the nuclear translocation of the GR, were evaluated by means of Western blot analysis. Results: FP alone increases and salmeterol alone does not affect T-cell apoptosis. The combination of FP and salmeterol significantly increases PBT apoptosis in comparison with FP alone. FP at the lower concentration, when combined with salmeterol, is equivalent to FP at the higher concentration in inducing PBT apoptosis. The synergy in the induction of cell apoptosis is associated with more efficient activation of caspases 8 and 3. FP plus salmeterol is also able to synergistically reduce the expression of phosphorylated IkBa, thus limiting nuclear factor kB activation. The synergy was related to an increased nuclear translocation of the GR. Conclusion: This study shows that the combination of FP and salmeterol is able to control PBT activation in asthmatic patients more efficiently than FP alone and with a lower concentration of

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Section: Discussionsupporting

confidence: 80%

Synergistic effects of fluticasone propionate and salmeterol on in vitro T-cell activation and apoptosis in asthma

Pace¹,

Gagliardo²,

Melis³

et al. 2004

Journal of Allergy and Clinical Immunology

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“…This induction of apoptosis has also been proposed to be the main effector mechanism for the beneficial effects of GC treatment in lymphoid malignancies. 5 Evidence is accumulating that non-apoptotic programmed cell death (PCD), such as mitotic catastrophe, senescence, necrosis-like PCD and autophagy, may also play a role in the tumor response to anticancer drugs. 6,7 Autophagy is a well-conserved process, regulating normal cytoplasmic and organelle turnover, and is characterized by the formation of autophagosomes: double-or multiple-membrane-surrounded cytoplasmic vesicles engulfing cytoplasmic organelles such as mitochondria and endoplasmic reticulum.…”

mentioning

confidence: 99%

Cell death induced by dexamethasone in lymphoid leukemia is mediated through initiation of autophagy

et al. 2009

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Glucocorticoids are fundamental drugs used in the treatment of lymphoid malignancies with apoptotic cell death as the hitherto proposed mechanism of action. Recent studies, however, showed that an alternative mode of cell death, autophagy, is involved in the response to anticancer drugs. The specific role of autophagy and its relationship to apoptosis remains, nevertheless, controversial: it can either lead to cell survival or can function in cell death. We show that dexamethasone induced autophagy upstream of apoptosis in acute lymphoblastic leukemia cells. Inhibition of autophagy by siRNA-mediated repression of Beclin 1 expression inhibited apoptosis showing an important role of autophagy in dexamethasone-induced cell death. Dexamethasone treatment caused an upregulation of promyelocytic leukemia protein, PML, its complex formation with protein kinase B or Akt and a PML-dependent Akt dephosphorylation. Initiation of autophagy and the onset of apoptosis were both dependent on these events. PML knockout thymocytes were resistant to dexamethasone-induced death and upregulation of PML correlated with the ability of dexamethasone to kill primary leukemic cells. Our data reveal key mechanisms of dexamethasone-induced cell death that may inform the development of improved treatment protocols for lymphoid malignancies.

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“…28,29 The anti-apoptotic Bcl-2 was able to protect against apoptosis, but not against the anti-proliferative responses induced by GC. 30 Furthermore, inhibition of the anti-apoptotic Bcl-xL sensitized T-ALL cells to Dex-induced apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Dexamethasone-induced apoptosis in acute lymphoblastic leukemia involves differential regulation of Bcl-2 family members

Laane¹,

Panaretakis²,

Pokrovskaja³

et al. 2007

Haematologica

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Recent insights into the mechanism of glucocorticosteroid-induced apoptosis

Cited by 265 publications

References 113 publications

Synergistic effects of fluticasone propionate and salmeterol on in vitro T-cell activation and apoptosis in asthma

Synergistic effects of fluticasone propionate and salmeterol on in vitro T-cell activation and apoptosis in asthma

Cell death induced by dexamethasone in lymphoid leukemia is mediated through initiation of autophagy

Dexamethasone-induced apoptosis in acute lymphoblastic leukemia involves differential regulation of Bcl-2 family members

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