Danazol induces apoptosis and cytotoxicity of leukemic cells alone and in combination with purine nucleoside analogs in chronic lymphocytic leukemia

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• 作者：Monika Podhorecka ; Arkadiusz Macheta ; Sylwia Chocholska…
• 关键词：Apoptosis ; Bendamustine ; Chronic lymphocytic leukemia ; Cladribine ; Cytotoxicity ; Danazol ; Fludarabine
• 刊名：Annals of Hematology
• 出版年：2016
• 出版时间：February 2016
• 年：2016
• 卷：95
• 期：3
• 页码：425-435
• 全文大小：1,663 KB
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• 作者单位：Monika Podhorecka (1)
  Arkadiusz Macheta (1)
  Sylwia Chocholska (1)
  Agnieszka Bojarska-Junak (2)
  Agnieszka Szymczyk (1)
  Aneta Goracy (1)
  Anna Dmoszynska (1)
  Marek Hus (1)
  
  1. Department of Haematooncology and Bone Marrow Transplantation, Medical University of Lublin, Staszica 11, 20-081, Lublin, Poland
  2. Department of Clinical Immunology, Medical University of Lublin, Lublin, Poland
  
• 刊物类别：Medicine
• 刊物主题：Medicine & Public Health
  Hematology
  Oncology
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1432-0584

文摘

Recently, great progress has been achieved in the treatment of chronic lymphocytic leukemia (CLL). However, some patients, particularly older patients with comorbidities or with relapsed/refractory leukemia, still have limited therapeutic options. There is an urgent need to discover less toxic and more effective drugs for CLL patients. Applying new modalities or substances that are widely used for the treatment of other diseases has been reported to improve results in CLL treatment. This study aimed to assess the non-chemotherapeutic drug danazol for its potential to destroy leukemic cells. Leukemic cells, obtained from the peripheral blood and bone marrow of 23 CLL patients, were cultured in the presence of danazol and its combination with the purine nucleoside analogs fludarabine and cladribine and bendamustine. After 24 h of incubation, the rate of apoptosis indicated by active caspase-3 expression, and cytotoxicity indicated by forward light scatter and light scatter analysis, was assessed by flow cytometry. We also measured expression of apoptosis-regulating proteins of BCL family and active caspase 9 and active caspase 8 expressions in leukemic cells. Danazol had a caspase-dependent pro-apoptotic and cytotoxic effect on leukemic cells in a tumor-specific manner. The mechanisms of its action appear to be complex and should be precisely established; however, induction of apoptosis involving both mitochondrial and receptor cascades appears to be most probable. Danazol showed a synergic effect with cladribine, an additive effect with fludarabine, and an infra-additive effect with bendamustine. The rate of danazol-induced apoptosis and cytotoxicity did not differ between patients with better and worse prognostic markers. Our results indicate that danazol may be a potential therapeutic agent for CLL patients alone and in combination with purine analogs. Keywords Apoptosis Bendamustine Chronic lymphocytic leukemia Cladribine Cytotoxicity Danazol Fludarabine