Glucocorticoid resistance in childhood leukaemia: mechanisms and modulation

Haarman, Eric G.; Kaspers, Gertjan J. L.; Veerman, A. J. P.

doi:10.1046/j.1365-2141.2003.04189.x

Cited by 49 publications

(51 citation statements)

References 117 publications

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“…Although the issue of glucocorticoid resistance in RA treatment is less well studied than in cancer treatment (24,31), it has been recognized to be of clinical importance in RA treatment as well (32,33). In the treatment of patients with systemic lupus erythematosus, drug combinations of HCQ and prednisone have also been used without apparent signs of drug resistance (34).…”

Section: Discussionmentioning

confidence: 99%

Acquired resistance to chloroquine in human CEM T cells is mediated by multidrug resistance–associated protein 1 and provokes high levels of cross‐resistance to glucocorticoids

Oerlemans

Heijden

Vink

et al. 2006

Arthritis & Rheumatism

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Objective. To explore the onset and molecular mechanism of resistance to the antimalarial diseasemodifying antirheumatic drug (DMARD) chloroquine (CQ) in human CEM T cells.Methods. Human CEM cells were used as an in vitro model system to study the development of CQ resistance by growing cells in stepwise increasing concentrations of CQ.Results. Over a period of 6 months, CEM cell lines developed 4-5-fold resistance to CQ. CQ resistance was associated with the specific overexpression of multidrug resistance-associated protein 1 (MRP-1), an ATP-driven drug efflux pump. This was illustrated by 1) overexpression of MRP-1 by Western blotting and 2) the complete reversal of CQ resistance by the MRP-1 transport inhibitors MK571 and probenecid. Importantly, CQ-resistant CEM cells retained full sensitivity to other DMARDs, including methotrexate, leflunomide, cyclosporin A, and sulfasalazine, but exhibited a high level of cross-resistance (>1,000-fold) to the glucocorticoid dexamethasone. The mechanistic basis for the latter was associated with aberrant signaling via the cAMP-protein kinase A pathway, since the cAMP-inducing agent forskolin reversed dexamethasone resistance. Finally, CQ-resistant CEM cells displayed a markedly reduced capacity to release proinflammatory cytokines (tumor necrosis factor ␣) and chemokines (interleukin-8).Conclusion. Induction of overexpression of the multidrug resistance efflux transporter MRP-1 can emerge after long-term exposure to CQ and results in CQ resistance and collateral resistance to dexamethasone. These findings warrant further detailed investigations into the possible role of MRP-1 and other members of the superfamily of drug efflux pumps in diminishing the efficacy of DMARDs in rheumatoid arthritis treatment.

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Section: Discussionmentioning

confidence: 99%

Acquired resistance to chloroquine in human CEM T cells is mediated by multidrug resistance–associated protein 1 and provokes high levels of cross‐resistance to glucocorticoids

Oerlemans

Heijden

Vink

et al. 2006

Arthritis & Rheumatism

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“…There are many reports in the literature on GC resistance by downstream mechanisms in experimental systems; however, in most, if not all, cases, the observed phenotype might be better referred to as reduced sensitivity rather than true long-term resistance with maintained clonogenic survival in the continuous presence of the drug. In patients, glutathione and glutathione S-transferase expression (reviewed in Tissing et al 8 and Haarman et al 86 ) and alterations in the 'Bcl-2 rheostat' have attracted considerable attention. Regarding the latter, expression of Bcl-2 family members was investigated in numerous studies with somewhat conflicting outcomes.…”

Section: 'Downstream Mechanisms' Interfering With Death or Activatingmentioning

confidence: 99%

“…5,8,9,52,86 ) Conceptually, they may be grouped into 'upstream' and 'downstream' mechanisms. The former concern the GR, its ligand and GR-associated proteins that control its function, and have the potential to affect most, if not all, GC effects while the latter interfere with, and affect, only individual GC responses.…”

Section: Mechanisms Of Resistance To Gc-induced Apoptosismentioning

confidence: 99%

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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“…Different cell types within one organism respond differently to GC exposure varying from induction to inhibition of apoptosis, or even induction of cell proliferation. [53][54][55][56] Very little is known about the mechanisms that determine which GC-responsive genes are transactivated or transrepressed upon the activation of the GR. It does not seem unlikely that structural changes in the DNA-binding domain influence this process.…”

Section: Figurementioning

confidence: 99%

Glucocorticoid receptor alpha, beta and gamma expression vs in vitro glucocorticod resistance in childhood leukemia

et al. 2004

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Alternative splicing of the primary glucocorticoid receptor (GR) transcript, resulting in glucocorticoid receptor alpha GRa, glucocorticoid receptor beta GRb and glucocorticoid receptor gamma GRc, may influence glucocorticoid (GC) resistance in childhood leukemia. To test this hypothesis, we determined GRa/b protein and GRa/b/c mRNA expression levels in 43 initial acute lymphoblastic leukemia (iALL), 10 initial myeloid leukemia (iAML), 11 relapsed ALL (rALL) samples and one rAML sample. The results were correlated with in vitro GC resistance. GRa mRNA correlated with protein expression (q ¼ 0.39-0.56, Po0.05), but the protein to mRNA ratio was median 2.2-fold lower in rALL than in iALL (Po0.05). GRb mRNA was median 137-fold lower than GRa mRNA and correlated with GRa mRNA expression (q ¼ 0.71, Po0.0001). GRb could not be detected at the protein level. GRc accounted for a median of 2.8% (range 0.95-7.4%) of all GR transcripts. GRa (protein and mRNA) and GRb (mRNA) expressions or GRa/GRb ratios did not correlate with in vitro GC resistance in iALL, but GRc (mRNA) did (q ¼ 0.52, P ¼ 0.007). These results suggest that GRb is not involved in GC resistance in childhood leukemia. The association between GRc expression and in vitro GC resistance in iALL and the decreased protein/mRNA ratio in rALL, a subgroup resistant to GCs, warrants further exploration.

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Glucocorticoid resistance in childhood leukaemia: mechanisms and modulation

Cited by 49 publications

References 117 publications

Acquired resistance to chloroquine in human CEM T cells is mediated by multidrug resistance–associated protein 1 and provokes high levels of cross‐resistance to glucocorticoids

Acquired resistance to chloroquine in human CEM T cells is mediated by multidrug resistance–associated protein 1 and provokes high levels of cross‐resistance to glucocorticoids

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

Glucocorticoid receptor alpha, beta and gamma expression vs in vitro glucocorticod resistance in childhood leukemia

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