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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.
- Source :
-
Investigational new drugs [Invest New Drugs] 2011 Dec; Vol. 29 (6), pp. 1264-75. Date of Electronic Publication: 2010 Jul 08. - Publication Year :
- 2011
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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 G(1) 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.
- Subjects :
- Antigens, CD34 metabolism
Antineoplastic Agents chemistry
Apoptosis Regulatory Proteins
Cell Line, Tumor
Cytarabine pharmacology
Drug Synergism
Etoposide pharmacology
Humans
Inhibitor of Apoptosis Proteins metabolism
Leukemia pathology
Protein Binding
Stem Cells metabolism
TNF-Related Apoptosis-Inducing Ligand pharmacology
X-Linked Inhibitor of Apoptosis Protein metabolism
Antineoplastic Agents pharmacology
Apoptosis drug effects
Intracellular Signaling Peptides and Proteins metabolism
Leukemia drug therapy
Mitochondrial Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1573-0646
- Volume :
- 29
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Investigational new drugs
- Publication Type :
- Academic Journal
- Accession number :
- 20614162
- Full Text :
- https://doi.org/10.1007/s10637-010-9475-6