title: Cyclic AMP can promote APL progression and protect myeloid leukemia cells against anthracycline-induced apoptosis.
abstract: We show that cyclic AMP (cAMP) elevating agents protect blasts from patients with acute promyelocytic leukemia (APL) against death induced by first-line anti-leukemic anthracyclines like daunorubicin (DNR). The cAMP effect was reproduced in NB4 APL cells, and shown to depend on activation of the generally cytoplasmic cAMP-kinase type I (PKA-I) rather than the perinuclear PKA-II. The protection of both NB4 cells and APL blasts was associated with (inactivating) phosphorylation of PKA site Ser118 of pro-apoptotic Bad and (activating) phosphorylation of PKA site Ser133 of the AML oncogene CREB. Either event would be expected to protect broadly against cell death, and we found cAMP elevation to protect also against 2-deoxyglucose, rotenone, proteasome inhibitor and a BH3-only mimetic. The in vitro findings were mirrored by the findings in NSG mice with orthotopic NB4 cell leukemia. The mice showed more rapid disease progression when given cAMP-increasing agents (prostaglandin E2 analog and theophylline), both with and without DNR chemotherapy. The all-trans retinoic acid (ATRA)-induced terminal APL cell differentiation is a cornerstone in current APL treatment and is enhanced by cAMP. We show also that ATRA-resistant APL cells, believed to be responsible for treatment failure with current ATRA-based treatment protocols, were protected by cAMP against death. This suggests that the beneficial pro-differentiating and non-beneficial pro-survival APL cell effects of cAMP should be weighed against each other. The results suggest also general awareness toward drugs that can affect bone marrow cAMP levels in leukemia patients.
authors: Department of Biomedicine, University of Bergen, Bergen, Norway.
authors: G
authors: G
authors: Gausdal
authors: A
authors: A
authors: Wergeland
authors: J
authors: J
authors: Skavland
authors: E
authors: E
authors: Nguyen
authors: F
authors: F
authors: Pendino
authors: N
authors: N
authors: Rouhee
authors: E
authors: E
authors: McCormack
authors: L
authors: L
authors: Herfindal
authors: R
authors: R
authors: Kleppe
authors: U
authors: U
authors: Havemann
authors: F
authors: F
authors: Schwede
authors: O
authors: O
authors: Bruserud
authors: B T
authors: BT
authors: Gjertsen
authors: M
authors: M
authors: Lanotte
authors: E
authors: E
authors: Ségal-Bendirdjian
authors: S O
authors: SO
authors: Døskeland
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000819:agonists / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D054743:Cyclic AMP-Dependent Protein Kinase Type I / Q000378:metabolism; D054746:Cyclic AMP-Dependent Protein Kinase Type II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D003630:Daunorubicin / Q000494:pharmacology* / Q000627:therapeutic use; D015232:Dinoprostone / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D018450:Disease Progression; D018922:HL-60 Cells; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D013806:Theophylline / Q000494:pharmacology / Q000627:therapeutic use; D014183:Transplantation, Heterologous; D014212:Tretinoin / Q000494:pharmacology / Q000627:therapeutic use; D051025:bcl-Associated Death Protein / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D017362:Cyclic AMP Response Element-Binding Protein; D034741:RNA, Small Interfering; D051025:bcl-Associated Death Protein; D014212:Tretinoin; D013806:Theophylline; D000242:Cyclic AMP; D054743:Cyclic AMP-Dependent Protein Kinase Type I; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D015232:Dinoprostone; D015056:1-Methyl-3-isobutylxanthine; D003630:Daunorubicin