2-Aminophenoxazine-3-one-induced apoptosis via generation of reactive oxygen species followed by c-jun N-terminal kinase activation in the human glioblastoma cell line LN229

  • Authors:
    • Xiao-Fang Che
    • Shota Moriya
    • Chun-Lei Zheng
    • Akihisa Abe
    • Akio Tomoda
    • Keisuke Miyazawa
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  • Published online on: September 4, 2013     https://doi.org/10.3892/ijo.2013.2088
  • Pages: 1456-1466
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Abstract

2-Aminophenoxazine-3-one (Phx-3) induces apoptosis in several types of cancer cell lines. However, the mechanism of apoptosis induction by Phx-3 has not been fully elucidated. In this study, we investigated the anticancer effects of Phx-3 in the glioblastoma cell line LN229 and analyzed its molecular mechanism. The results indicated that 6- and 20-h treatment with Phx-3 significantly induced apoptosis in LN229 cells, with downregulation of survivin and XIAP. Both ERK and JNK, which are the members of the MAPK family, were activated after treatment with Phx-3. Inhibition of ERK using the specific inhibitor U0126 blocked the Phx-3-induced apoptosis only in part. However, inhibition of JNK using the specific inhibitor SP600125 completely prevented Phx-3-induced apoptosis and restored the phosphorylation states of ERK to the control levels. Enhanced generation of reactive oxygen species (ROS) was detected after 3-h treatment with Phx-3. In addition, the ROS scavenger melatonin almost completely blocked Phx-3-induced JNK activation and apoptosis. This suggests that JNK activation was mediated by Phx-3-induced ROS generation. Although SP600125 and melatonin completely blocked the reduction of mitochondrial membrane potential after a 3-h treatment with Phx-3, extension of Phx-3 exposure time to 20 h resulted in no cancelation of mitochondrial depolarization by these reagents. These reagents also had little effect on the decreased expression of survivin and XIAP during a 3-20-h exposure to Phx-3. These results indicate that the production of ROS following JNK activation is the main axis of Phx-3-induced apoptosis in LN229 cells for short-term exposure to Phx-3, whereas alternative mechanism(s) appear to be involved in apoptosis induction during long-term exposure to Phx-3.
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November 2013
Volume 43 Issue 5

Print ISSN: 1019-6439
Online ISSN:1791-2423

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APA
Che, X., Moriya, S., Zheng, C., Abe, A., Tomoda, A., & Miyazawa, K. (2013). 2-Aminophenoxazine-3-one-induced apoptosis via generation of reactive oxygen species followed by c-jun N-terminal kinase activation in the human glioblastoma cell line LN229. International Journal of Oncology, 43, 1456-1466. https://doi.org/10.3892/ijo.2013.2088
MLA
Che, X., Moriya, S., Zheng, C., Abe, A., Tomoda, A., Miyazawa, K."2-Aminophenoxazine-3-one-induced apoptosis via generation of reactive oxygen species followed by c-jun N-terminal kinase activation in the human glioblastoma cell line LN229". International Journal of Oncology 43.5 (2013): 1456-1466.
Chicago
Che, X., Moriya, S., Zheng, C., Abe, A., Tomoda, A., Miyazawa, K."2-Aminophenoxazine-3-one-induced apoptosis via generation of reactive oxygen species followed by c-jun N-terminal kinase activation in the human glioblastoma cell line LN229". International Journal of Oncology 43, no. 5 (2013): 1456-1466. https://doi.org/10.3892/ijo.2013.2088