Protein kinase inhibitors flavopiridol and 7-hydroxy-staurosporine down-regulate antiapoptosis proteins in B-cell chronic lymphocytic leukemia.
Compounds that inhibit protein kinases are currently undergoing clinical evaluation for the treatment of a variety of malignancies. The kinase inhibitors flavopiridol and 7 hydroxy-staurosporine (UCN-01) were examined for their effects on B-cell chronic lymphocytic leukemia (B-CLL) cells in vitro (n = 49). Flavopiridol and UCN-01 induced concentration-dependent apoptosis of most B-CLL samples tested, with greater than 50% cell killing occurring at concentrations of less than 1 mcmol/L, and with flavopiridol displaying more potent activity than UCN-01. Flavopiridol (0.1 mcmol/L) and UCN-01 (1 mcmol/L) also induced striking decreases in the levels of the antiapoptosis proteins Mcl-1, X-linked inhibitor of apoptosis (XIAP), and BAG-1 in nearly all cases of B-CLL and of Bcl-2 in approximately half of B-CLL specimens evaluated. In contrast, expression of the proapoptotic proteins Bax and Bak was not significantly influenced by these kinase inhibitors. Flavopiridol-induced decreases in the levels of antiapoptosis proteins Mcl-1 and XIAP preceded apoptosis and were not substantially affected by the addition of caspase inhibitors to cultures. In contrast, UCN-01-stimulated decreases in antiapoptosis proteins were slower, occurred concurrently with apoptosis, and were partially prevented by caspase inhibitors. The findings suggest that flavopiridol and UCN-01 induce apoptosis of B-CLL cells through different mechanisms. The potent apoptotic activities of flavopiridol and UCN-01 against cultured B-CLL cells suggest that they may be effective as single agents in the treatment of B-CLL or for sensitizing B-CLL cells to conventional cytotoxic drugs. (Blood. 2000;96:393-397)
Kitada
S
S
Burnham Institute, Program on Apoptosis and Cell Death Research, La Jolla, CA 92307, USA.
Zapata
J M
JM
Andreeff
M
M
Reed
J C
JC
D000470:Alkaloids / Q000494:pharmacology*; D017209:Apoptosis; D002352:Carrier Proteins / Q000378:metabolism; D053938:DNA Fragmentation; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D020287:In Situ Nick-End Labeling; D007700:Kinetics; D015448:Leukemia, B-Cell / Q000378:metabolism* / Q000473:pathology; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors; D011506:Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D019311:Staurosporine / Q000031:analogs & derivatives; D014157:Transcription Factors; D014407:Tumor Cells, Cultured; D051636:X-Linked Inhibitor of Apoptosis Protein
D000470:Alkaloids; C091732:BCL2-associated athanogene 1 protein; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014157:Transcription Factors; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C077990:alvocidib; C054852:7-hydroxystaurosporine; D019311:Staurosporine