In acute promyelocytic leukemia NB4 cells, the synthetic retinoid CD437 induces contemporaneously apoptosis, a caspase-3-mediated degradation of PML/RARalpha protein and the PML retargeting on PML-nuclear bodies.
CD437-induced apoptosis has been investigated in NB4, a human t(15;17) acute promyelocytic leukemia (APL) cell line, and in the retinoic acid (RA)-resistant NB4-R1 derivative subclone. Both NB4 and NB4-R1 cells underwent rapid apoptosis in response to low doses of CD437 (10(-7)M). This apoptosis did not require the activation of classical retinoid receptors and like arsenic (As)-induced apoptosis was preceded by the rapid activation of a caspase-3-like enzymatic activity as indicated by the increase of DEVD-pNA hydrolytic activity, by the processing of procaspase-3 protein and by the cleavage of poly(ADP-ribose) polymerase (PARP). Furthermore, it was demonstrated that the caspase-3-like proteolytic activity is responsible for the degradation of both the PML/RARalpha oncogenic protein and the normal RARalpha proteins. In CD437-treated cells, PML proteins were not degraded and PML relocalization on PMLNBs occurred in all the cells before death. CD437-induced apoptosis and receptor degradation were proteasome independent and not influenced either by inhibitors of protein tyrosine kinases (PTK), protein tyrosine phosphatases (PTPases) and serine proteases or by glutathione levels. Moreover, our data suggested that as for As2O3-induced apoptosis Bc12 modulation is not significant for CD437-induced apoptosis of NB4 cells. Since CD437 induces in vitro the rapid apoptosis of both RA-sensitive and -resistant APL cells, it could represent the first retinoid potentially able to eradicate in vivo malignant leukemia blasts.
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CNRS UPR 9051 Pathologie Cellulaire, Aspects Moleculaires de Viraux, Laboratoire Associé No. 11 au Comité de Paris de la Ligue contre le Cancer, Hôpital Saint-Louis, France.
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D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology; D053148:Caspase 3; D020169:Caspases / Q000502:physiology*; D002460:Cell Line; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000473:pathology*; D009363:Neoplasm Proteins / Q000378:metabolism*; D009687:Nuclear Proteins; D010087:Oxides / Q000494:pharmacology; D000071156:Promyelocytic Leukemia Protein; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D017382:Reactive Oxygen Species; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism*; D025521:Tumor Suppressor Proteins
D000970:Antineoplastic Agents; D001152:Arsenicals; C099555:CD 437; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D010087:Oxides; D000071156:Promyelocytic Leukemia Protein; D019253:Proto-Oncogene Proteins c-bcl-2; C000607071:RARA protein, human; D017382:Reactive Oxygen Species; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D000077237:Arsenic Trioxide