Enhancement of hyperthermia-induced apoptosis by a new synthesized class of benzocycloalkene compounds |
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Authors: | Da-Yong Yu Yuji Matsuya Qing-Li Zhao Kanwal Ahmed Zheng-Li Wei Takeshi Hori Hideo Nemoto Takashi Kondo |
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Institution: | (1) Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan;(2) Laboratory of Medicinal Chemistry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan;(3) Department of Orthopaedic Surgery, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan |
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Abstract: | The aim of this study was to examine whether, a new synthesized class of benzocycloalkene derivatives (BCs), enhances apoptosis
induced by hyperthermia. The combined effects of hyperthermia (44°C, 20 min) and BCs on apoptosis in human lymphoma U937 cells
were investigated. Among the tested compounds (BC1 ∼ 9), the combined treatment of 10 μM BC2 or BC4 and hyperthermia showed
the largest potency to induce DNA fragmentation at 6 h after hyperthermia. And enhancement of hyperthermia-induced apoptosis
by BC2 or BC4 in a dose-dependent manner was observed. When the cells were treated first with BC2 or BC4 at a nontoxic concentration
of 20 μM, and exposed to hyperthermia afterwards, a significant enhancement of heat-induced apoptosis was evidenced by DNA
fragmentation, morphological changes and phosphatidylserine externalization. Flow cytometry revealed an increase of intracellular
superoxide due to BC2 or BC4, which was further increased when hyperthermia was combined. Mitochondrial membrane potential
was decreased and the activation of caspase-3 and caspase-8 was enhanced in the cells treated with the combination. The activation
of Bid, but no change of Bax and Bcl-2 were observed after the combined treatment. The release of cytochrome c from mitochondria
to cytosol, which was induced by hyperthermia, was enhanced by BC2 or BC4. An increase in the intracellular Ca2+ concentration Ca2+]i, externalization of Fas, and decrease in Hsp70 were observed following the combined treatment. These results indicate that
the intracellular superoxide generated by BC2 or BC4 is involved in the enhancement of apoptosis through Fas-mitochondria
caspase and Ca2+]i-dependent pathways, and a decrease in Hsp70 also contributed to the enhancement of apoptosis. |
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Keywords: | Apoptosis Hyperthermia Reactive oxygen species Calcium |
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