Enhancement of macrosphelide-induced apoptosis by mild hyperthermia.
Hyperthermia is a useful adjunct in cancer therapy as it can increase the effectiveness and decrease the toxicity of currently available cancer treatments such as chemotherapy and radiation. In the present study, we investigated whether 41 degrees C hyperthermia (mild HT) for 20 min can enhance macrosphelide (MS5)-induced apoptosis in human lymphoma U937 cells. Our results revealed that, compared with MS5 (5 microM) and mild HT alone, the combined treatment exhibited significant enhancement in apoptosis at 6 h, which was evaluated by observing morphological changes and DNA fragmentation. Marked increase in the reactive oxygen species (ROS) generation was observed immediately after the combined treatment. Significant increase in Fas externalization, caspase-8 and caspase-3 activation, and loss of mitochondrial membrane potential (MMP) was found after the combined treatment compared with MS5 and mild HT alone. Moreover, this combination can also alter the expression of apoptosis-related proteins as evident by the cleavage of Bid and down-regulation of Bcl-2 while no change in the expression of Bax was observed. Furthermore, an immediate rise in the intracellular calcium ion ([Ca(2+)]i) concentration was observed after the combined treatment, which continuously increased in a time-dependent manner. In addition, mild HT treatment alone also increases [Ca(2+)]i concentration without inducing apoptosis. Our data indicate that early increase in ROS generation is mainly responsible for the enhancement of apoptosis after the combined treatment.
Ahmed
K
K
Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
Zhao
Q-L
QL
Matsuya
Y
Y
Yu
D-Y
DY
Salunga
T L
TL
Nemoto
H
H
Kondo
T
T
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism / Q000528:radiation effects; D002118:Calcium / Q000378:metabolism / Q000528:radiation effects; D053148:Caspase 3 / Q000378:metabolism / Q000528:radiation effects; D053181:Caspase 8 / Q000378:metabolism / Q000528:radiation effects; D003131:Combined Modality Therapy; D005786:Gene Expression Regulation / Q000528:radiation effects; D006571:Heterocyclic Compounds / Q000627:therapeutic use; D006358:Hot Temperature; D006801:Humans; D006979:Hyperthermia, Induced; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000528:radiation effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000528:radiation effects; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000528:radiation effects; D013997:Time Factors; D020298:U937 Cells; D051028:bcl-2-Associated X Protein / Q000378:metabolism / Q000528:radiation effects
D000970:Antineoplastic Agents; C494826:BAX protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D006571:Heterocyclic Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; C097798:macrosphelide A; C505530:CASP8 protein, human; D053148:Caspase 3; D053181:Caspase 8; D002118:Calcium