Enhancement of radiation-induced apoptosis of human lymphoma U937 cells by sanazole.
Sanazole has been tested clinically as a hypoxic cell radiosensitizer. In this study, we determined whether sanazole enhances the radiation-induced apoptosis of human lymphoma U937 cells. Our results revealed that, compared with 10 mM sanazole or radiation alone, the combination of both resulted in a significant enhancement of apoptosis after 6 h, which was evaluated on the basis of DNA fragmentation, morphological changes, and phosphatidylserine externalization. Sanazole alone enhanced intracellular superoxide and hydrogen peroxide formation, which further increased when the cells were irradiated. Significant enhancement of Fas externalization, loss of mitochondrial membrane potential (MMP), and activation of caspase-3 and caspase-8 were observed after the combined treatment. Moreover, this combination could also enhance Bid activation, reduction of Hsp70 expression level and release of cytochrome c from the mitochondria to the cytosol. An immediate increase in the intracellular Ca(2+) concentration ([Ca(2+)](i)) was observed after the combined treatment. These results suggest that the intracellular superoxide and peroxide generated by sanazole might be involved in the enhancement of radiation-induced apoptosis, and that these effects are associated with modulation of the Fas-mitochondria-caspase-dependent pathway, an increase in [Ca(2+)](i), and a decrease in the Hsp70 expression levels.
Yu
Da-Yong
DY
Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani 2630, Toyama, 930-0194, Japan.
Zhao
Qing-Li
QL
Wei
Zheng-Li
ZL
Nomura
Takaharu
T
Kashiwakura
Ikuo
I
Kagiya
Tsutomu V
TV
Kondo
Takashi
T
D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000528:radiation effects; D020169:Caspases / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects / Q000528:radiation effects; D004354:Drug Screening Assays, Antitumor; D005089:Exocytosis / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000528:radiation effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000528:radiation effects; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000528:radiation effects; D018384:Oxidative Stress / Q000187:drug effects; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*; D020298:U937 Cells; D019014:fas Receptor / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C491901:FAS protein, human; D011838:Radiation-Sensitizing Agents; D017382:Reactive Oxygen Species; D014230:Triazoles; D019014:fas Receptor; C072690:AK 2123; D020169:Caspases