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Synergistic effects of chemotherapeutic drugs in lymphoma cells are associated with down-regulation of inhibitor of apoptosis proteins (IAPs), prostate-apoptosis-response-gene 4 (Par-4), death-associated protein (Daxx) and with enforced caspase activation
- Source :
- Biochemical Pharmacology. 66:711-724
- Publication Year :
- 2003
- Publisher :
- Elsevier BV, 2003.
-
Abstract
- Cytotoxic drugs mediate apoptotic tumor cell death by influencing key regulator proteins of programmed cell death. In clinical practice cytotoxic drug combinations are desired to potentiate tumor cell kill and to minimize side effects. Nevertheless, the molecular mechanisms underlying synergistic and antagonistic effects on tumor cells are still poorly understood. In order to elucidate these molecular mechanisms we established models of synergistic and antagonistic drug combinations within the same lymphoma cell lines. By combination index method we demonstrated that bendamustine in combination with either doxorubicin or mitoxantrone caused antagonistic effects on disruption of mitochondrial membrane potential as well as on the rate of apoptosis. In contrast the combination of bendamustine with cladribine acted synergistically on these parameters. By using the IC(50) (dosages causing 50% rate of apoptosis) the synergistic effect of the combination of bendamustine and cladribine was associated with an enhanced mitochondrial release of cytochrome c and Smac/DIABLO, by down-regulation of x-linked inhibitor of apoptosis (XIAP), cIAP1, Par-4 and Daxx as well as by a significantly increased activation of caspases-3, -6, -7, -8 and -9. At the same rate of apoptosis (IC(50)), the antagonistic combinations did not increase the release of cytochrome c or Smac/DIABLO, nor down-regulate the expression of XIAP, cIAP1, Par-4 and Daxx, nor increase the activation of caspases. The role of down-regulation of IAPs and of enforced caspase activation for synergism in this model was supported by the observation, that broad spectrum inhibition of caspases re-established expression of XIAP. Our study is the first to outline the molecular alterations caused by synergistic and antagonistic drug combinations within the same lymphoma cell model. The above described mechanisms were already assessable at a point where the effects of synergistic or antagonistic combinations could not yet be discriminated quantitatively by the level of apoptosis rate of the lymphoma cells.
- Subjects :
- Programmed cell death
Lymphoma
Ubiquitin-Protein Ligases
Down-Regulation
Apoptosis
Cytochrome c Group
X-Linked Inhibitor of Apoptosis Protein
Inhibitor of apoptosis
Biochemistry
Inhibitor of Apoptosis Proteins
Mitochondrial Proteins
Death-associated protein 6
Antineoplastic Combined Chemotherapy Protocols
Tumor Cells, Cultured
Bendamustine Hydrochloride
Humans
Cytotoxic T cell
Caspase
Adaptor Proteins, Signal Transducing
Pharmacology
biology
Cytochrome c
Intracellular Signaling Peptides and Proteins
Nuclear Proteins
Proteins
Drug Synergism
XIAP
Enzyme Activation
Cytoskeletal Proteins
Proto-Oncogene Proteins c-bcl-2
Doxorubicin
Caspases
Nitrogen Mustard Compounds
biology.protein
Cancer research
Cladribine
Mitoxantrone
Tumor Suppressor Protein p53
Apoptosis Regulatory Proteins
Carrier Proteins
Co-Repressor Proteins
Molecular Chaperones
Subjects
Details
- ISSN :
- 00062952
- Volume :
- 66
- Database :
- OpenAIRE
- Journal :
- Biochemical Pharmacology
- Accession number :
- edsair.doi.dedup.....a92953fb84ed9d8f7d3214a06177d23d