Apoptosis

, Volume 13, Issue 3, pp 448–461 | Cite as

Enhancement of hyperthermia-induced apoptosis by a new synthesized class of benzocycloalkene compounds

  • Da-Yong Yu
  • Yuji Matsuya
  • Qing-Li Zhao
  • Kanwal Ahmed
  • Zheng-Li Wei
  • Takeshi Hori
  • Hideo Nemoto
  • Takashi Kondo
Original Paper
First Online:

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.

Keywords

Apoptosis Hyperthermia Reactive oxygen species Calcium 
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Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Da-Yong Yu
    • 1
  • Yuji Matsuya
    • 2
  • Qing-Li Zhao
    • 1
  • Kanwal Ahmed
    • 1
  • Zheng-Li Wei
    • 1
  • Takeshi Hori
    • 3
  • Hideo Nemoto
    • 2
  • Takashi Kondo
    • 1
  1. 1.Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical SciencesUniversity of ToyamaToyamaJapan
  2. 2.Laboratory of Medicinal Chemistry, Graduate School of Medicine and Pharmaceutical SciencesUniversity of ToyamaToyamaJapan
  3. 3.Department of Orthopaedic Surgery, Graduate School of Medicine and Pharmaceutical SciencesUniversity of ToyamaToyamaJapan

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