Novel second mitochondria-derived activator of caspases (Smac) mimetic compounds sensitize human leukemic cell lines to conventional chemotherapeutic drug-induced and death receptor-mediated apoptosis

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• 作者：Federica Servida (1) fservida@hotmail.com
  Daniele Lecis (2)
  Cinzia Scavullo (1)
  Carmelo Drago (3)
  Pierfausto Seneci (34)
  Carmelo Carlo-Stella (6)
  Leonardo Manzoni (35)
  Elio Polli (1)
  Giorgio Lambertenghi Deliliers (17)
  Domenico Delia (2)
  Francesco Onida (17)
• 关键词：Leukemia &#8211 ; Apoptosis &#8211 ; Smac ; mimetics &#8211 ; XIAP &#8211 ; IAP &#8211 ; TRAIL
• 刊名：Investigational New Drugs
• 出版年：2011
• 出版时间：December 2011
• 年：2011
• 卷：29
• 期：6
• 页码：1264-1275
• 全文大小：505.8 KB
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• 作者单位：1. Fondazione Matarelli, Dipartimento di Farmacologia Chemioterapia e Tossicologia Medica, Universit脿 degli Studi di Milano, Via Vanvitelli 32, 20129 Milan, Italy2. Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy3. Centro Interdisciplinare di Studi Biomolecolari e Applicazioni Industriali (CISI), Milan, Italy4. Dipartimento di Chimica Organica e Industriale, Universit脿 degli Studi di Milano, Milan, Italy5. CNR鈥揑stituto di Scienze e Tecnologie Molecolari, Milan, Italy6. Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori and University of Milano, Milan, Italy7. U.O. Ematologia 1- CTMO, Fondazione IRCCS Ca鈥?Granda Ospedale Maggiore Policlinico di Milano, Universit脿 degli Studi di Milano, Milan, Italy
• 刊物类别：Medicine
• 刊物主题：Medicine & Public Health
  Oncology
  Pharmacology and Toxicology
  
• 出版者：Springer Netherlands
• ISSN：1573-0646

文摘

The Inhibitor of Apoptosis Proteins (IAPs) are important regulators of programmed cell death. XIAP is the most potent among them and is over-expressed in several hematological malignancies. Its activity is endogenously antagonized by SMAC/DIABLO, and also by small molecules mimicking Smac that can induce apoptosis in tumor cells. Here we describe the activity of 56 newly synthesized Smac-mimetics in human leukemic cell lines and normal CD34+ progenitor cells. Our compounds bind to XIAP with high affinity, reduce the levels of cIAP1 and are cytotoxic at nanomolar or low micromolar concentrations. Furthermore, the Smac-mimetics synergize with Cytarabine, Etoposide and especially with TRAIL in combination treatments. Apoptosis activation was clearly detectable by the occurrence of sub G₁ apoptotic peak and the accumulation of cleaved PARP, caspase 8 and caspase 3. Interestingly, the down-regulation of XIAP sensitized Jurkat cells to drugs too, confirming the role of this protein in drug-resistance. In conclusion, while being very active in leukemic cells, our Smac-mimetics have modest effects on normal hematopoietic progenitors, suggesting their promising therapeutic potential as a new class of anticancer drugs in onco-hematology, particularly when combined with TRAIL, to overcome the resistance of cancer cells.