Abstract
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.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- ALL:
-
acute lymphoblastic leukemia
- GC:
-
glucocorticoid(s)
- GR:
-
glucocorticoid receptor
References
Ashwell JD, Lu FW and Vacchio MS (2000) Glucocorticoids in T cell development and function. Annu. Rev. Immunol. 18: 309–345
Cidlowski JA, King KL, Evans-Storms RB, Montague JW, Bortner CD and Hughes Jr FM (1996) The biochemistry and molecular biology of glucocorticoid-induced apoptosis in the immune system. Recent Prog. Horm. Res. 51: 457–490
Jondal M, Pazirandeh A and Okret S (2001) A role for glucocorticoids in the thymus? Trends Immunol. 22: 185–186
Gaynon PS and Carrel AL (1999) Glucocorticosteroid therapy in childhood acute lymphoblastic leukemia. Adv. Exp. Med. Biol. 457: 593–605
Renner K, Ausserlechner MJ and Kofler R (2003) A conceptual view on glucocorticoid-induced apoptosis, cell cycle arrest and glucocorticoid resistance in lymphoblastic leukemia. Curr. Mol. Med. 3: 707–717
Ausserlechner MJ, Obexer P, Böck G, Geley S and Kofler R (2004) Cyclin D3 and c-myc control glucocorticoid-induced cell cycle arrest but not apoptosis in lymphoblastic leukemia cells. Cell Death Differ. 11: 165–174
McKay LI and Cidlowski JA (1999) Molecular control of immune/inflammatory responses: interactions between nuclear factor-kappa B and steroid receptor-signaling pathways. Endocr. Rev. 20: 435–459
Tissing WJ, Meijerink JP, den Boer ML and Pieters R (2003) Molecular determinants of glucocorticoid sensitivity and resistance in acute lymphoblastic leukemia. Leukemia 17: 17–25
Schaaf MJ and Cidlowski JA (2002) Molecular mechanisms of glucocorticoid action and resistance. J. Steroid Biochem. Mol. Biol. 83: 37–48
Greenstein S, Ghias K, Krett NL and Rosen ST (2002) Mechanisms of glucocorticoid-mediated apoptosis in hematological malignancies. Clin. Cancer Res. 8: 1681–1694
Distelhorst CW (2002) Recent insights into the mechanism of glucocorticosteroid-induced apoptosis. Cell Death Differ. 9: 6–19
Planey SL and Litwack G (2000) Glucocorticoid-induced apoptosis in lymphocytes. Biochem. Biophys. Res. Commun. 279: 307–312
Kofler R (2000) The molecular basis of glucocorticoid-induced apoptosis of lymphoblastic leukemia cells. Histochem. Cell Biol. 114: 1–7
O’Brien CA, Jia D, Plotkin LI, Bellido T, Powers CC, Stewart SA, Manolagas SC and Weinstein RS (2004) Glucocorticoids act directly on osteoblasts and osteocytes to induce their apoptosis and reduce bone formation and strength. Endocrinology 145: 1835–1841
Sapolsky RM, Romero LM and Munck AU (2000) How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocr. Rev. 21: 55–89
Druilhe A, Letuve S and Pretolani M (2003) Glucocorticoid-induced apoptosis in human eosinophils: mechanisms of action. Apoptosis 8: 481–495
Hammer S, Sauer B, Spika I, Schraut C, Kleuser B and Schafer-Korting M (2004) Glucocorticoids mediate differential anti-apoptotic effects in human fibroblasts and keratinocytes via sphingosine-1-phosphate formation. J. Cell Biochem. 91: 840–851
Yamaguchi S, Ohsaki Y, Nishigaki Y, Toyoshima E and Kikuchi K . (1999) Inhibition of human small cell lung cancer cell growth by methylprednisolone. Int. J. Oncol. 15: 1185–1190
Wessely O, Deiner EM, Beug H and Von Lindern M (1997) The glucocorticoid receptor is a key regulator of the decision between self-renewal and differentiation in erythroid progenitors. EMBO J. 16: 267–280
Stankova J, Turcotte S, Harris J and Rola-Pleszczynski M (2002) Modulation of leukotriene b(4) receptor-1 expression by dexamethasone: potential mechanism for enhanced neutrophil survival. J. Immunol. 168: 3570–3576
Amsterdam A and Sasson R (2002) The anti-inflammatory action of glucocorticoids is mediated by cell type specific regulation of apoptosis. Mol. Cell. Endocrinol. 189: 1–9
Fan W, Sui M and Huang Y (2004) Glucocorticoids selectively inhibit paclitaxel-induced apoptosis: mechanisms and its clinical impact. Curr. Med. Chem. 11: 403–411
Bloom JW, Chacko J, Lohman IC, Halonen M, Martinez FD and Miesfeld RL (2004) Differential control of eosinophil survival by glucocorticoids. Apoptosis 9: 97–104
Buttgereit F and Scheffold A (2002) Rapid glucocorticoid effects on immune cells. Steroids 67: 529–534
Laudet V and Gronemeyer H (2002) The Nuclear Receptor Facts Book. (London: Academic Press) pp. 1–462
Pratt WB and Toft DO (1997) Steroid receptor interactions with heat shock protein and immunophilin chaperones. Endocr. Rev. 18: 306–360
Geley S, Fiegl M, Hartmann BL and Kofler R (1996) Genes mediating glucocorticoid effects and mechanisms of their regulation. Rev. Physiol. Biochem. Pharmacol. 128: 1–97
Maurer M, Trajanoski Z, Frey G, Hiroi N, Galon J, Willenberg HS, Gold PW, Chrousos GP, Scherbaum WA and Bornstein SR (2001) Differential gene expression profile of glucocorticoids, testosterone, and dehydroepiandrosterone in human cells. Horm. Metab Res. 33: 691–695
Tonko M, Ausserlechner MJ, Bernhard D, Helmberg A and Kofler R (2001) Gene expression profiles of proliferating versus G1/G0 arrested human leukemia cells suggest a mechanism for glucocorticoid-induced apoptosis. FASEB J. 15: 693–699
Obexer P, Certa U, Kofler R and Helmberg A (2001) Expression profiling of glucocorticoid-treated T-ALL cell lines: rapid repression of multiple genes involved in RNA-, protein- and nucleotide synthesis. Oncogene 20: 4324–4336
Planey SL, Abrams MT, Robertson NM and Litwack G (2003) Role of apical caspases and glucocorticoid-regulated genes in glucocorticoid-induced apoptosis of pre-B leukemic cells. Cancer Res. 63: 172–178
Wang Z, Malone MH, Thomenius MJ, Zhong F, Xu F and Distelhorst CW (2003) Dexamethasone-induced gene 2 (dig2) is a novel pro-survival stress gene induced rapidly by diverse apoptotic signals. J. Biol. Chem. 278: 27053–27058
Wang Z, Malone MH, He H, McColl KS and Distelhorst CW (2003) Microarray analysis uncovers the induction of the pro-apoptotic BH3-only protein Bim in multiple models of glucocorticoid induced apoptosis. J. Biol. Chem. 278: 23861–23867
Chauhan D, Auclair D, Robinson EK, Hideshima T, Li G, Podar K, Gupta D, Richardson P, Schlossman RL, Krett N, Chen LB, Munshi NC and Anderson KC (2002) Identification of genes regulated by dexamethasone in multiple myeloma cells using oligonucleotide arrays. Oncogene 21: 1346–1358
Chauhan S, Leach CH, Kunz S, Bloom JW and Miesfeld RL (2003) Glucocorticoid regulation of human eosinophil gene expression. J. Steroid Biochem. Mol. Biol. 84: 441–452
Webb MS, Miller AL, Johnson BH, Fofanov Y, Li T, Wood TG and Thompson EB (2003) Gene networks in glucocorticoid-evoked apoptosis of leukemic cells. J. Steroid Biochem. Mol. Biol. 85: 183–193
Yoshida NL, Miyashita T, U M, Yamada M, Reed JC, Sugita Y and Oshida T (2002) Analysis of gene expression patterns during glucocorticoid-induced apoptosis using oligonucleotide arrays. Biochem. Biophys. Res. Commun. 293: 1254–1261
Mittelstadt PR and Ashwell JD (2003) Disruption of glucocorticoid receptor exon 2 yields a ligand-responsive C-terminal fragment that regulates gene expression. Mol. Endocrinol. 17: 1534–1542
Valverde MA and Parker MG (2002) Classical and novel steroid actions: a unified but complex view. Trends Biochem. Sci. 27: 172–173
Gametchu B and Watson CS (2002) Correlation of membrane glucocorticoid receptor levels with glucocorticoid-induced apoptotic competence using mutant leukemic and lymphoma cells lines. J. Cell Biochem. 87: 133–146
Reichardt HM, Kaestner KH, Tuckermann J, Kretz O, Wessely O, Bock R, Gass P, Schmid W, Herrlich P, Angel P and Schütz G (1998) DNA binding of the glucocorticoid receptor is not essential for survival. Cell 93: 531–541
Hala M, Hartmann BL, Böck G, Geley S and Kofler R (1996) Glucocorticoid receptor gene defects and resistance to glucocorticoid-induced apoptosis in human leukemic cell lines. Int. J. Cancer 68: 663–668
Geley S, Hartmann BL, Hala M, Strasser-Wozak EMC, Kapelari K and Kofler R (1996) Resistance to glucocorticoid-induced apoptosis in human T-cell acute lymphoblastic leukemia CEM-C1 cells is due to insufficient glucocorticoid receptor expression. Cancer Res. 56: 5033–5038
Helmberg A, Auphan N, Caelles C and Karin M (1995) Glucocorticoid-induced apoptosis of human leukemic cells is caused by the repressive function of the glucocorticoid receptor. EMBO J. 14: 452–460
Reichardt HM, Umland T, Bauer A, Kretz O and Schutz G (2000) Mice with an increased glucocorticoid receptor gene dosage show enhanced resistance to stress and endotoxic shock. Mol. Cell. Biol. 20: 9009–9017
Pazirandeh A, Xue Y, Prestegaard T, Jondal M and Okret S (2002) Effects of altered glucocorticoid sensitivity in the T-cell lineage on thymocyte and T-cell homeostasis. FASEB J. 16: 727–729
Brunet CL, Gunby RH, Benson RSP, Hickman JA, Watson AJM and Brady G (1998) Commitment to cell death measured by loss of clonogenicity is separable from the appearance of apoptotic markers. Cell Death Differ. 5: 107–115
Wallace AD and Cidlowski JA (2001) Proteasome-mediated glucocorticoid receptor degradation restricts transcriptional signaling by glucocorticoids. J. Biol. Chem. 276: 42714–42721
Gomi M, Moriwaki K, Katagiri S, Kurata Y and Thompson EB (1990) Glucocorticoid effects on myeloma cells in culture: correlation of growth inhibition with induction of glucocorticoid receptor messenger RNA. Cancer Res. 50: 1873–1878
Pedersen KB and Vedeckis WV (2003) Quantification and glucocorticoid regulation of glucocorticoid receptor transcripts in two human leukemic cell lines. Biochemistry 42: 10978–10990
Ramdas J, Liu W and Harmon JM (1999) Glucocorticoid-induced cell death requires autoinduction of glucocorticoid receptor expression in human leukemic T cells. Cancer Res. 59: 1378–1385
Kofler R, Schmidt S, Kofler A and Ausserlechner MJ (2003) Resistance to glucocorticoid-induced apoptosis in lymphoblastic leukemia. J. Endocrinol. 178: 19–27
Riml S, Schmidt S, Ausserlechner MJ, Geley S and Kofler R (2004) Glucocorticoid receptor heterozygosity combined with lack of receptor auto-induction causes glucocorticoid resistance in Jurkat acute lymphoblastic leukemia cells. Cell Death Differ 11 (S1): S65–S72
Dieken ES and Miesfeld RL (1992) Transcriptional transactivation functions localized to the glucocorticoid receptor N terminus are necessary for steroid induction of lymphocyte apoptosis. Mol. Cell. Biol. 12: 589–597
Thompson EB, Nazareth LV, Thulasi R, Ashraf J, Harbour D and Johnson BH (1992) Glucocorticoids in malignant lymphoid cells: gene regulation and the minimum receptor fragment for lysis. J. Steroid Biochem. Mol. Biol. 41: 273–282
Smith KGC, Strasser A and Vaux DL (1996) CrmA expression in T lymphocytes of transgenic mice inhibits CD95 (Fas/APO-1)-transduced apoptosis, but does not cause lymphadenopathy or autoimmune disease. EMBO J. 15: 5167–5176
Geley S, Hartmann BL, Kapelari K, Egle A, Villunger A, Heidacher D, Greil R, Auer B and Kofler R (1997) The interleukin 1b-converting enzyme inhibitor crmA prevents Apo1/fas- but not glucocorticoid-induced poly(ADP-ribose) polymerase cleavage and apoptosis in lymphoblastic leukemia cells. FEBS Lett. 402: 36–40
D'Adamio F, Zollo O, Moraca R, Ayroldi E, Bruscoli S, Bartoli A, Cannarile L, Migliorati G and Riccardi C (1997) A new dexamethasone-induced gene of the leucine zipper family protects T lymphocytes from TCR/CD3-activated cell death. Immunity 7: 803–812
Marchetti MC, Di Marco B, Cifone G, Migliorati G and Riccardi C (2003) Dexamethasone-induced apoptosis of thymocytes: role of glucocorticoid receptor-associated Src kinase and caspase-8 activation. Blood 101: 585–593
Cecconi F, Alvarez-Bolado G, Meyer BI, Roth KA and Gruss P (1998) Apaf1 (CED-4 homolog) regulates programmed cell death in mammalian development. Cell 94: 727–737
Yoshida H, Kong YY, Yoshida R, Elia AJ, Hakem A, Hakem R, Penninger JM and Mak TW (1998) Apaf1 is required for mitochondrial pathways of apoptosis and brain development. Cell 94: 739–750
Hakem R, Hakem A, Duncan GS, Henderson JT, Woo M, Soengas MS, Elia A, De la Pompa JL, Kagi D, Khoo W, Potter J, Yoshida R, Kaufman SA, Lowe SW, Penninger JM and Mak TW (1998) Differential requirement for Caspase 9 in apoptotic pathways in vivo. Cell 94: 339–352
Kuida K, Haydar TF, Kuan CY, Gu Y, Taya C, Karasuyama H, Su MSS, Rakic P and Flavell RA (1998) Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking Caspase 9. Cell 94: 325–337
Rathmell JC, Lindsten T, Zong WX, Cinalli RM and Thompson CB (2002) Deficiency in Bak and Bax perturbs thymic selection and lymphoid homeostasis. Nat. Immunol. 3: 932–939
Bouillet P, Metcalf D, Huang DC, Tarlinton DM, Kay TW, Kontgen F, Adams JM and Strasser A (1999) Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science 286: 1735–1738
Villunger A, Michalak EM, Coultas L, Mullauer F, Bock G, Ausserlechner MJ, Adams JM and Strasser A (2003) p53- and drug-induced apoptotic responses mediated by BH3-only proteins puma and noxa. Science 302: 1036–1038
Knudson CM, Tung KSK, Tourtellotte WG, Brown GAJ and Korsmeyer SJ (1995) Bax-deficient mice with lymphoid hyperplasia and male germ cell death. Science 270: 96–99
Yin XM, Wang K, Gross A, Zhao Y, Zinkel S, Klocke B, Roth KA and Korsmeyer SJ (1999) Bid-deficient mice are resistant to Fas-induced hepatocellular apoptosis. Nature 400: 886–891
Grillot DA, Merino R and Nunez G (1995) Bcl-XL displays restricted distribution during T cell development and inhibits multiple forms of apoptosis but not clonal deletion in transgenic mice. J. Exp. Med. 182: 1973–1983
Hartmann BL, Geley S, Löffler M, Hattmannstorfer R, Strasser-Wozak EMC, Auer B and Kofler R (1999) Bcl-2 interferes with the execution phase, but not upstream events, in glucocorticoid-induced leukemia apoptosis. Oncogene 18: 713–719
Feinman R, Koury J, Thames M, Barlogie B, Epstein J and Siegel DS (1999) Role of NF-kappaB in the rescue of multiple myeloma cells from glucocorticoid-induced apoptosis by bcl-2. Blood 93: 3044–3052
Han J, Flemington C, Houghton AB, Gu Z, Zambetti GP, Lutz RJ, Zhu L and Chittenden T (2001) Expression of bbc3, a pro-apoptotic BH3-only gene, is regulated by diverse cell death and survival signals. Proc. Natl. Acad. Sci. USA 98: 11318–11323
Casale F, Addeo R, D’Angelo V, Indolfi P, Poggi V, Morgera C, Crisci S and Di Tullio MT (2003) Determination of the in vivo effects of prednisone on Bcl-2 family protein expression in childhood acute lymphoblastic leukemia. Int. J. Oncol. 22: 123–128
Chauhan D, Hideshima T, Pandey P, Treon S, Teoh G, Raje N, Rosen S, Krett N, Husson H, Avraham S, Kharbanda S and Anderson KC (1999) RAFTK/PYK2-dependent and -independent apoptosis in multiple myeloma cells. Oncogene 18: 6733–6740
Chauhan D, Pandey P, Hideshima T, Treon S, Raje N, Davies FE, Shima Y, Tai YT, Rosen S, Avraham S, Kharbanda S and Anderson KC (2000) SHP2 mediates the protective effect of interleukin-6 against dexamethasone-induced apoptosis in multiple myeloma cells. J. Biol. Chem. 275: 27845–27850
Auphan N, DiDonato JA, Rosette C, Helmberg A and Karin M (1995) Immunosuppression by glucocorticoids: inhibition of NF-kappaB activity through induction of IkappaB synthesis. Science 270: 286–290
Ayroldi E, Migliorati G, Bruscoli S, Marchetti C, Zollo O, Cannarile L, D'Adamio F and Riccardi C (2001) Modulation of T-cell activation by the glucocorticoid-induced leucine zipper factor via inhibition of nuclear factor kappaB. Blood 98: 743–753
Mittelstadt PR and Ashwell JD (2001) Inhibition of AP-1 by the glucocorticoid-inducible protein GILZ. J. Biol. Chem. 276: 29603–29610
Herrlich P (2001) Cross-talk between glucocorticoid receptor and AP-1. Oncogene 20: 2465–2475
Caldenhoven E, Liden J, Wissink S, Van de Stolpe A, Raaijmakers J, Koenderman L, Okret S, Gustafsson J and Van der Saag PT (1995) Negative cross-talk between RelA and the glucocorticoid receptor: a possible mechanism for the antiinflammatory action of glucocorticoids. Mol. Endocrinol. 9: 401–412
Fernandez A, Kiefer J, Fosdick L and McConkey DJ (1995) Oxygen radical production and thiol depletion are required for Ca2+-mediated endogenous endonuclease activation in apoptotic thymocytes. J. Immunol. 155: 5133–5139
Tome ME and Briehl MM (2001) Thymocytes selected for resistance to hydrogen peroxide show altered antioxidant enzyme profiles and resistance to dexamethasone-induced apoptosis. Cell Death Differ. 8: 953–961
Distelhorst CW and Dubyak G (1998) Role of calcium in glucocorticosteroid-induced apoptosis of thymocytes and lymphoma cells: resurrection of old theories by new findings. Blood 91: 731–734
Matsuyama S and Reed JC (2000) Mitochondria-dependent apoptosis and cellular pH regulation. Cell Death Differ. 7: 1155–1165
Gomez-Angelats M, Bortner CD and Cidlowski JA (2000) Cell volume regulation in immune cell apoptosis. Cell Tissue Res. 301: 33–42
Haarman EG, Kaspers GJ and Veerman AJ (2003) Glucocorticoid resistance in childhood leukaemia: mechanisms and modulation. Br. J. Haematol. 120: 919–929
Raivio T, Palvimo JJ, Kannisto S, Voutilainen R and Janne OA (2002) Transactivation assay for determination of glucocorticoid bioactivity in human serum. J. Clin. Endocrinol. Metab 87: 3740–3744
Gottesman MM, Fojo T and Bates SE (2002) Multidrug resistance in cancer: role of ATP-dependent transporters. Nat. Rev. Cancer 2: 48–58
Karssen AM, Meijer OC, van dS, I, Lucassen PJ, de Lange EC, de Boer AG and De Kloet ER (2001) Multidrug resistance P-glycoprotein hampers the access of cortisol but not of corticosterone to mouse and human brain. Endocrinology 142: 2686–2694
Bourgeois S, Gruol DJ, Newby RF and Rajah FM (1993) Expression of an mdr gene is associated with a new form of resistance to dexamethasone-induced apoptosis. Mol. Endocrinol. 7: 840–851
den Boer ML, Pieters R, Kazemier KM, Rottier MM, Zwaan CM, Kaspers GJ, Janka-Schaub G, Henze G, Creutzig U, Scheper RJ and Veerman AJ (1998) Relationship between major vault protein/lung resistance protein, multidrug resistance-associated protein, P-glycoprotein expression, and drug resistance in childhood leukemia. Blood 91: 2092–2098
Rabbitt EH, Lavery GG, Walker EA, Cooper MS, Stewart PM and Hewison M (2002) Prereceptor regulation of glucocorticoid action by 11beta-hydroxysteroid dehydrogenase: a novel determinant of cell proliferation. FASEB J. 16: 36–44
Strasser-Wozak EMC, Hattmannstorfer R, Hála M, Hartmann BL, Fiegl M, Geley S and Kofler R (1995) Splice site mutation in the glucocorticoid receptor gene causes resistance to glucocorticoid-induced apoptosis in a human acute leukemic cell line. Cancer Res. 55: 348–353
Soufi M, Kaiser U, Schneider A, Beato M and Westphal HM (1995) The DNA and steroid binding domains of the glucocorticoid receptor are not altered in mononuclear cells of treated CLL patients. Exp. Clin. Endocrinol. Diabetes 103: 175–183
Krett NL, Pillay S, Moalli PA, Greipp PR and Rosen ST (1995) A variant glucocorticoid receptor messenger RNA is expressed in multiple myeloma patients. Cancer Res. 55: 2727–2729
De Lange P, Segeren CM, Koper JW, Wiemer E, Sonneveld P, Brinkmann AO, White A, Brogan IJ, De Jong FH and Lamberts SW (2001) Expression in hematological malignancies of a glucocorticoid receptor splice variant that augments glucocorticoid receptor-mediated effects in transfected cells. Cancer Res. 61: 3937–3941
Oakley RH, Jewell CM, Yudt MR, Bofetiado DM and Cidlowski JA (1999) The dominant negative activity of the human glucocorticoid receptor beta isoform. Specificity and mechanisms of action. J. Biol. Chem. 274: 27857–27866
De Castro M, Elliot S, Kino T, Bamberger C, Karl M, Webster E and Chrousos GP (1996) The non-ligand binding beta-isoform of the human glucocorticoid receptor (hGR beta): tissue levels, mechanism of action, and potential physiologic role. Mol. Med. 2: 597–607
Webster JC, Oakley RH, Jewell CM and Cidlowski JA (2001) Proinflammatory cytokines regulate human glucocorticoid receptor gene expression and lead to the accumulation of the dominant negative beta isoform: a mechanism for the generation of glucocorticoid resistance. Proc. Natl. Acad. Sci. USA 98: 6865–6870
Longui CA, Vottero A, Adamson PC, Cole DE, Kino T, Monte O and Chrousos GP (2000) Low glucocorticoid receptor alpha/beta ratio in T-cell lymphoblastic leukemia. Horm. Metab. Res. 32: 401–406
Hecht K, Carlstedt-Duke J, Stierna P, Gustafsson JÅ, Brönnegård M and Wikström AC (1997) Evidence that the b-isoform of the human glucocorticoid receptor does not act as a physiologically significant repressor. J. Biol. Chem. 272: 26659–26664
Haarman EG, Kaspers GJ, Pieters R, Rottier MM and Veerman AJ (2004) Glucocorticoid receptor alpha, beta and gamma expression vs in vitro glucocorticod resistance in childhood leukemia. Leukemia 18: 530–537
Pui CH, Dahl GV, Rivera G, Murphy SB and Costlow ME (1984) The relationship of blast cell glucocorticoid receptor levels to response to single-agent steroid trial and remission response in children with acute lymphoblastic leukemia. Leuk. Res. 8: 579–585
Kato GJ, Quddus FF, Shuster JJ, Boyett J, Pullen JD, Borowitz MJ, Whitehead VM, Crist WM and Leventhal BG (1993) High glucocorticoid receptor content of leukemic blasts is a favorable prognostic factor in childhood acute lymphoblastic leukemia. Blood 82: 2304–2309
Lauten M, Cario G, Asgedom G, Welte K and Schrappe M (2003) Protein expression of glucocorticoid receptor in childhood acute lmphoblastic leukaemia. Haematologica 88: 1253–1258
Csoka M, Bocsi J, Falus A, Szalai C, Klujber V, Szende B and Schuler D (1997) Glucocorticoid-induced apoptosis and treatment sensitivity in acute lymphoblastic leukemia of children. Pediatr. Hematol. Oncol. 14: 433–442
Salomons GS, Brady HJM, Verwijs-Janssen M, Van den Berg JD, Hart AAM, Van den Berg H, Behrendt H, Hählen K and Smets LA (1997) The Baxa:Bcl-2 ratio modulates the response to dexamethasone in leukaemic cells and is highly variable in childhood acute leukaemia. Int. J. Cancer 71: 959–965
Stahnke K, Eckhoff S, Mohr A, Meyer LH and Debatin KM (2003) Apoptosis induction in peripheral leukemia cells by remission induction treatment in vivo: selective depletion and apoptosis in a CD34+ subpopulation of leukemia cells. Leukemia 17: 2130–2139
Salomons GS, Smets LA, Verwijs-Janssen M, Hart AA, Haarman EG, Kaspers GJ, Wering EV, Der Does-Van Den Berg AV and Kamps WA (1999) Bcl-2 family members in childhood acute lymphoblastic leukemia: relationships with features at presentation, in vitro and in vivo drug response and long-term clinical outcome. Leukemia 13: 1574–1580
Haarman EG, Kaspers GJ, Pieters R, Van Zantwijk CH, Broekema GJ, Hahlen K and Veerman AJ (1999) BCL-2 expression in childhood leukemia versus spontaneous apoptosis, drug induced apoptosis, and in vitro drug resistance. Adv. Exp. Med. Biol. 457: 325–333
Broome HE, Yu AL, Diccianni M, Camitta BM, Monia BP and Dean NM (2002) Inhibition of Bcl-xL expression sensitizes T-cell acute lymphoblastic leukemia cells to chemotherapeutic drugs. Leuk. Res. 26: 311–316
Liu Q and Gazitt Y (2003) Potentiation of dexamethasone, taxol and Ad-p53-induced apoptosis by Bcl-2 anti-sense oligodeoxynucleotides in drug-resistant multiple myeloma cells. Blood 101: 4105–4114
Reiter A, Schrappe M, Ludwig W-D, Hiddemann W, Sauter S, Henze G, Zimmermann M, Lampert F, Havers W, Niethammer D, Odenwald E, Ritter J, Mann G, Welte K, Gadner H and Riehm H (1994) Chemotherapy in 998 unselected childhood acute lymphoblastic leukemia patients. Results and conclusions of the multicenter trial ALL-BFM 86. Blood 84: 3122–3133
Dordelmann M, Reiter A, Borkhardt A, Ludwig WD, Gotz N, Viehmann S, Gadner H, Riehm H and Schrappe M (1999) Prednisone response is the strongest predictor of treatment outcome in infant acute lymphoblastic leukemia. Blood 94: 1209–1217
Arico M, Basso G, Mandelli F, Rizzari C, Colella R, Barisone E, Zanesco L, Rondelli R, Pession A and Masera G (1995) Good steroid response in vivo predicts a favorable outcome in children with T-cell acute lymphoblastic leukemia. The Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP). Cancer 75: 1684–1693
Schrappe M, Arico M, Harbott J, Biondi A, Zimmermann M, Conter V, Reiter A, Valsecchi MG, Gadner H, Basso G, Bartram CR, Lampert F, Riehm H and Masera G (1998) Philadelphia chromosome-positive (Ph+) childhood acute lymphoblastic leukemia: good initial steroid response allows early prediction of a favorable treatment outcome. Blood 92: 2730–2741
Geley S, Hartmann BL, Hattmannstorfer R, Löffler M, Ausserlechner MJ, Bernhard D, Sgonc R, Strasser-Wozak EMC, Ebner M, Auer B and Kofler R (1997) P53-induced apoptosis in the human T-ALL cell line CCRF-CEM. Oncogene 15: 2429–2437
Clarke AR, Purdie CA, Harrison DJ, Morris RG, Bird CC, Hooper ML and Wyllie AH (1993) Thymocyte apoptosis induced by p53-dependent and independent pathways. Nature 362: 849–852
Buckley AR, Krumenacker JS, Buckley DJ, Leff MA, Magnuson NS, Reed JC, Miyashita T, De Jong G and Gout PW (1997) Butyrate-induced reversal of dexamethasone resistance in autonomous rat Nb2 lymphoma cells. Apoptosis 2: 518–528
Stromberg T, Dimberg A, Hammarberg A, Carlson K, Osterborg A, Nilsson K and Jernberg-Wiklund H (2004) Rapamycin sensitizes multiple myeloma cells to apoptosis induced by dexamethasone. Blood 103: 3138–3147
Hideshima T, Chauhan D, Shima Y, Raje N, Davies FE, Tai YT, Treon SP, Lin B, Schlossman RL, Richardson P, Muller G, Stirling DI and Anderson KC (2000) Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood 96: 2943–2950
Hideshima T, Richardson P, Chauhan D, Palombella VJ, Elliott PJ, Adams J and Anderson KC (2001) The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res. 61: 3071–3076
Rose AL, Smith BE and Maloney DG (2002) Glucocorticoids and rituximab in vitro: synergistic direct antiproliferative and apoptotic effects. Blood 100: 1765–1773
Anderson KC (2003) Moving disease biology from the lab to the clinic. Cancer 97: 796–801
Breslin MB, Geng CD and Vedeckis WV (2001) Multiple promoters exist in the human GR gene, one of which is activated by glucocorticoids. Mol. Endocrinol. 15: 1381–1395
Acknowledgements
We thank C Achmüller, MJ Ausserlechner, C Biedermann, S Geley, A Helmberg, K Janjetovic, A Kofler, A Ploner, K Schröcksnadel and K Renner for stimulating discussions, and M Kat Occhipinti-Bender for editing the manuscript. This study is supported by grants from the Austrian Science Fund (SFB-F021, P14482-MOB), the European community (QLG1-CT-2001-01574) and the Austrian Ministry for Education, Science and Culture (GENAU-CHILD, GENAU-BIN). The Tyrolean Cancer Research Institute is supported by the ‘Tiroler Landeskrankenanstalten Ges.m.b.H. (TILAK)’, the ‘Tyrolean Cancer Society’, various businesses, financial institutions and the People of Tyrol.
Author information
Authors and Affiliations
Corresponding author
Additional information
Edited by G Melino
Rights and permissions
About this article
Cite this article
Schmidt, S., Rainer, J., Ploner, C. et al. Glucocorticoid-induced apoptosis and glucocorticoid resistance: molecular mechanisms and clinical relevance. Cell Death Differ 11 (Suppl 1), S45–S55 (2004). https://doi.org/10.1038/sj.cdd.4401456
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/sj.cdd.4401456
Keywords
This article is cited by
-
Dasatinib overcomes glucocorticoid resistance in B-cell acute lymphoblastic leukemia
Nature Communications (2023)
-
FAR591 promotes the pathogenesis and progression of SONFH by regulating Fos expression to mediate the apoptosis of bone microvascular endothelial cells
Bone Research (2023)
-
The rs1001179 SNP and CpG methylation regulate catalase expression in chronic lymphocytic leukemia
Cellular and Molecular Life Sciences (2022)
-
Effect of the uncoupling protein-2 (UCP-2) and nuclear receptor subfamily 3 group C member 1 (NR3C1) genes on treatment efficacy and survival in patients with multiple myeloma: a single-center study
BMC Research Notes (2021)
-
Integrative genomic analyses reveal mechanisms of glucocorticoid resistance in acute lymphoblastic leukemia
Nature Cancer (2020)
