Abstract
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.
Anti-Cancer Agents in Medicinal Chemistry
Title:BIBR 1532 Increases Arsenic Trioxide-mediated Apoptosis in Acute Promyelocytic Leukemia Cells: Therapeutic Potential for APL
Volume: 13 Issue: 7
Author(s): Davood Bashash, Seyed H.Ghaffari, Farhad Zaker, Maryam Kazerani, Kebria Hezave, Saeed Hassani, Masomeh Rostami, Kamran Alimoghaddam and Ardeshir Ghavamzadeh
Affiliation:
Keywords: Arsenic trioxide, BIBR 1532, Telomerase, Acute promyelocytic leukemia, Apoptosis, Combination therapy.
Abstract: 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.
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Bashash Davood, H.Ghaffari Seyed, Zaker Farhad, Kazerani Maryam, Hezave Kebria, Hassani Saeed, Rostami Masomeh, Alimoghaddam Kamran and Ghavamzadeh Ardeshir, BIBR 1532 Increases Arsenic Trioxide-mediated Apoptosis in Acute Promyelocytic Leukemia Cells: Therapeutic Potential for APL, Anti-Cancer Agents in Medicinal Chemistry 2013; 13 (7) . https://dx.doi.org/10.2174/18715206113139990126
DOI https://dx.doi.org/10.2174/18715206113139990126 |
Print ISSN 1871-5206 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5992 |
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