BIBR 1532 Increases Arsenic Trioxide-mediated Apoptosis in Acute Promyelocytic Leukemia Cells: Therapeutic Potential for APL
The current treatment of acute promyelocytic leukemia with arsenic trioxide (ATO) has increased long-lasting complete
remissions; however, a proportion of patients continues to die eventually as a result of disease recurrence. In an effort to enhance the
effectiveness of the APL treatment, we designed experiments to evaluate the effects of ATO in combination with the lead compound of
non-nucleoside inhibitor of telomerase, BIBR 1532. After combined treatments with BIBR 1532 and ATO, decreased cell viability index
with a concomitant increase in apoptotic cell death was observed in NB4 leukemic cells. Apoptosis induced by the combined treatments
was accompanied by elevated Bax/Bcl-2 molecular ratio and enhanced caspase 3 activation. Our study has also demonstrated that the
combined treatment suppressed NB4 cell proliferative capacity and inhibited telomerase activity probably via transcriptional suppression
of c-Myc and hTERT. In conclusion, this study may supply insight into the application of this new combination therapy to APL cells
intrinsically less sensitive to routine therapies and suggested a novel combination therapy for patients with more aggressive disease; those
who may not respond favorably to the arsenic mono-therapy.
Keywords: Arsenic trioxide, BIBR 1532, Telomerase, Acute promyelocytic leukemia, Apoptosis, Combination therapy.
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