Retinoid induced apoptosis in leukemia cells through a retinoic acid nuclear receptor-independent pathway.
Trans retinoic acid (RA) has proven to be a potent therapeutic agent in the treatment of acute promyelocytic leukemia. Unfortunately, other subtypes of acute myelogenous leukemia are resistant to the antiproliferative and differentiating effects of RA. In this report, we describe a novel retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN; CD437) that not only totally inhibits the proliferation of RA-resistant leukemic cell lines HL-60R and K562 but also induces apoptosis in these cells. Exposure of HL-60R to CD437 results in the rapid (within 30 minutes) increase of the cyclin-dependent kinase inhibitor p21(waf1/cip1) as well as GADD45 mRNA. Manifestations of CD437-mediated programmed cell death are noted within 2 hours, as indicated by both the cleavage and activation of the CPP32 protease and cleavage of poly (ADP-ribose) polymerase. This is followed by cleavage of bcl-2 and internucleosomal DNA degradation. HL-60R cells do not express the retinoid nuclear receptor RAR beta and RAR gamma and express a truncated RAR alpha. Thus, CD437 induction of p21(waf1/cip1) and GADD45 mRNAs and apoptosis occurs through a unique mechanism not involving the retinoid nuclear receptors. CD437 represents a unique retinoid with therapeutic potential in the treatment of myeloid leukemia.
Hsu
C A
CA
Department of Medicine and Cancer Center, University of Maryland at Baltimore and the Baltimore VA Medical Center, USA.
Rishi
A K
AK
Su-Li
X
X
Gerald
T M
TM
Dawson
M I
MI
Schiffer
C
C
Reichert
U
U
Shroot
B
B
Poirier
G G
GG
Fontana
J A
JA
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases; D002454:Cell Differentiation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics; D003546:Cysteine Endopeptidases / Q000378:metabolism; D053938:DNA Fragmentation; D019008:Drug Resistance, Neoplasm; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D018922:HL-60 Cells / Q000187:drug effects*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology; D009281:Naphthalenes / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids / Q000494:pharmacology*; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D000097642:GADD45 Proteins; D000097768:Retinoic Acid Receptor gamma
D000970:Antineoplastic Agents; D053148:Caspase 3; D020169:Caspases; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D003546:Cysteine Endopeptidases; D047908:Intracellular Signaling Peptides and Proteins; D009281:Naphthalenes; D009363:Neoplasm Proteins; D011065:Poly(ADP-ribose) Polymerases; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids; D014212:Tretinoin; D000097642:GADD45 Proteins; D000097768:Retinoic Acid Receptor gamma; C099555:CD 437; C493956:CDKN1A protein, human; C000607071:RARA protein, human; C082925:retinoic acid receptor beta; C505407:CASP3 protein, human