title: All trans retinoic acid induces apoptosis in acute promyelocytic NB4 cells when combined with isoquinolinediol, a poly(ADP-ribose) polymerase inhibitor.
abstract: NB4 cells, a model of acute promyelocytic leukemia have been shown to undergo granulocytic differentiation in response to all trans retinoic acid (ATRA), or monocytic differentiation in response to 1alpha,25 dihydroxyvitamin D(3) (1,25 D(3)) and phorbol ester. We have shown previously that the expression of poly(ADP-ribose) polymerase (PARP) is dramatically increased during monocytic differentiation and completely down-regulated during neutrophilic differentiation. Here we show that NB4 cells simultaneously treated with ATRA and isoquinolinediol (Iso-Q), a specific PARP inhibitor, fail to differentiate into neutrophils. Nitroblue tetrazolium (NBT) dye reduction was inhibited by 48% and neutrophil formation was reduced by 75%. NB4 cells treated with ATRA and Iso-Q instead showed features of apoptosis including nuclear condensation, DNA fragmentation, and PARP cleavage yielding a 85 kDa fragment. NB4 cells treated with ATRA in combination with 1,25 D(3), a monocytic differentiation inducer, while continuing to reduce NBT also failed to mature into neutrophils or monocytes and again showed features of apoptosis. Down-regulation of Bcl-2 protein expression was evident in NB4 cells treated with ATRA and ATRA in combination with Iso-Q or 1,25 D(3), but not in cells treated with a classic chemotherapeutic agent, arabinosycytosine, suggesting that Bcl-2 down-regulation is neither necessary, nor specific for apoptosis in this model.
authors.affiliation: Arthur and Sonia LaBatt Brain Tumor Research Center, Hospital for Sick Children, 555 University Avenue, Toronto, Canada.
authors.forename: D M
authors.initials: DM
authors.lastname: Berry
authors.forename: K
authors.initials: K
authors.lastname: Williams
authors.forename: K A
authors.initials: KA
authors.lastname: Meckling-Gill
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology; D002117:Calcitriol / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007546:Isoquinolines; D015473:Leukemia, Promyelocytic, Acute / Q000473:pathology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D011804:Quinolines / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D001549:Benzamides; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011804:Quinolines; C095653:1,5-dihydroxyisoquinoline; D014212:Tretinoin; C025160:3-aminobenzamide; D002117:Calcitriol