Molecular mechanisms of hyperthermia- and cisplatin-induced cytotoxicity in T cell leukemia.
BACKGROUND
The prognosis of early and very early relapse in acute lymphoblastic leukemia of childhood is still very poor unless a hematopoietic stem cell transplant is performed if a second remission can be achieved by induction chemotherapy. Therefore an intensification of chemotherapy is required.


METHODS
In the present study the molecular mechanisms of cisplatin- and/or hyperthermia-mediated cytotoxicity in CEM cells, a human T leukemia cell line, were investigated.


RESULTS
Both hyperthermia and cisplatin induced the activation of the effector caspases-3 and -6. However, caspase activation followed different time kinetics. While hyperthermia exerted maximum caspase activation immediately after application, cisplatin activated caspase-3 and -6 after 24 hours. At both time-points significant caspase-3 and -6 activation was observed when the cells were stimulated by a combination of heat and cisplatin. The application of z-VAD-fmk, a general caspase inhibitor, showed that hyperthermia mediated cytotoxicity mainly via caspase-dependent mechanisms, while cisplatin induced both caspase-dependent and -independent cytotoxicity. Time kinetic experiments revealed that hyperthermia induced cell death immediately after the heating pulse. In contrast, cisplatin-induced cell death had its maximum between 6 hours and 12 hours after the heating pulse. The combined application of heat and cisplatin induced two peaks of cytotoxicity, one immediately after the heating pulse and the other between 6 hours and 12 hours.


CONCLUSIONS
Hyperthermia and cisplatin induced cell death in T leukemic cells by different molecular mechanisms, which might explain the enhanced cisplatin-induced cytotoxicity by hyperthermia.
Mauz-Körholz
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C
Department of Pediatrics, University of Leipzig Medical Center, Oststr. 21-25, D-04317 Leipzig, Germany. mauc@medizin.uni-leipzig.de
Dietzsch
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S
Schippel
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Banning
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U
Körholz
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D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D053148:Caspase 3; D053178:Caspase 6; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002945:Cisplatin / Q000493:pharmacokinetics / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D006979:Hyperthermia, Induced / Q000379:methods*; D015458:Leukemia, T-Cell / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology / Q000628:therapy*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; C505407:CASP3 protein, human; C505514:CASP6 protein, human; D053148:Caspase 3; D053178:Caspase 6; D020169:Caspases; D002945:Cisplatin