Co-treatment with As2O3 enhances selective cytotoxic effects of STI-571 against Brc-Abl-positive acute leukemia cells.
By inhibiting the tyrosine kinase (TK) activity of Bcr-Abl, STI-571 induces differentiation and apoptosis of HL-60/Bcr-Abl (with ectopic expression of p185 Bcr-Abl) and K562 (containing endogenous expression of p210 Bcr-Abl) but not of the control HL-60 cells. Treatment with arsenic trioxide (As2O3) lowers Bcr-Abl protein levels and induces apoptosis of the Bcr-Abl-positive leukemic blasts (Blood 2000; 95: 1014). Here, we demonstrate that compared to treatment with STI-571 (0.25 to 1.0 microM) or As2O3 (0.5 to 2.0 microM) alone, combined treatment with As2O3 and STI-571 induced significantly more apoptosis of HL-60/Bcr-Abl and K562 but not HL-60/neo cells (P < 0.05). Combined treatment with As2O3 and STI-571 also resulted in greater reductions in the levels of Bcl-x(L), XIAP and Akt, and inhibition of Akt kinase activity. Co-treatment with As2O3 inhibited STI-571-induced hemoglobin, which was associated with the cleavage and downregulation of GATA-1 transcription factor involved in erythroid differentiation. These data demonstrate that a treatment strategy which combines an agent that lowers Bcr-Abl levels, eg As2O3, with an agent that inhibits Bcr-Abl TK activity, eg STI-571, can potently induce apoptosis and differentiation of Bcr-Abl-positive human leukemic cells.
Porosnicu
M
M
Interdisciplinary Oncology Program, Moffitt Cancer Center, University of South Florida, Tampa 33612, USA.
Nimmanapalli
R
R
Nguyen
D
D
Worthington
E
E
Perkins
C
C
Bhalla
K N
KN
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage*; D001549:Benzamides; D004357:Drug Synergism; D016044:Fusion Proteins, bcr-abl / Q000032:analysis*; D006454:Hemoglobins / Q000032:analysis; D006801:Humans; D000068877:Imatinib Mesylate; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology; D016177:Macrophage-1 Antigen / Q000032:analysis; D010087:Oxides / Q000008:administration & dosage*; D010879:Piperazines / Q000008:administration & dosage*; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000032:analysis; D011518:Proto-Oncogene Proteins / Q000032:analysis; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D011743:Pyrimidines / Q000008:administration & dosage*; D014407:Tumor Cells, Cultured; D051636:X-Linked Inhibitor of Apoptosis Protein; D051020:bcl-X Protein
D001152:Arsenicals; C494811:BCL2L1 protein, human; D001549:Benzamides; D006454:Hemoglobins; D016177:Macrophage-1 Antigen; D010087:Oxides; D010879:Piperazines; D011506:Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D051020:bcl-X Protein; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000077237:Arsenic Trioxide