Molecular determinants of glucocorticoid sensitivity and resistance in acute lymphoblastic leukemia.
Glucocorticoids (GC) are probably the most important drugs in the treatment of ALL. Despite the extensive use of GC for many years, little is known about the molecular mechanisms of sensitivity and resistance. This review summarizes the knowledge on GC cytotoxicity in leukemia. The relevance of polymorphisms, splice variants and the number and regulation of the GC receptor are discussed. The role of multidrug resistance proteins, glutathione and glutathione S-transferase is evaluated, as well as the influence of the different heat-shock chaperone (hsp 90 and 70) and co-chaperone proteins (BAG-1 and others) which form a complex together with the GC receptor. Finally, the transactivation and transrepression (via NF-kappa B and AP-1 binding) of a wide range of genes (like c-myc) which initiates the final apoptosis pathway are discussed and suggestions for future directions of research in ALL patients are given.
Tissing
W J E
WJ
University Hospital Rotterdam/Sophia Children's Hospital, Department of Paediatric Oncology/Hematology, Rotterdam, The Netherlands.
Meijerink
J P P
JP
den Boer
M L
ML
Pieters
R
R
D000208:Acute Disease; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D002648:Child; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D005938:Glucocorticoids / Q000494:pharmacology*; D005982:Glutathione Transferase / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D007945:Leukemia, Lymphoid / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D018832:Molecular Chaperones; D016328:NF-kappa B / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism
D004268:DNA-Binding Proteins; D005938:Glucocorticoids; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D016328:NF-kappa B; D016271:Proto-Oncogene Proteins c-myc; D011965:Receptors, Glucocorticoid; D018808:Transcription Factor AP-1; D005982:Glutathione Transferase