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

Federica Servida, Daniele Lecis, Cinzia Scavullo, Carmelo Drago, Pierfausto Seneci, Carmelo Carlo-Stella, Leonardo Manzoni, Elio Polli, Giorgio Lambertenghi Deliliers, Domenico Delia, Francesco Onida

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1264-1275
Number of pages12
JournalInvestigational New Drugs
Volume29
Issue number6
DOIs
Publication statusPublished - Dec 2011

Keywords

  • Apoptosis
  • IAP
  • Leukemia
  • Smac-mimetics
  • TRAIL
  • XIAP

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Oncology

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