Open Access

2-Aminophenoxazine-3-one induces cellular apoptosis by causing rapid intracellular acidification and generating reactive oxygen species in human lung adenocarcinoma cells

  • Authors:
    • Chun-Lei Zheng
    • Xiao-Fang Che
    • Shin-Ichi Akiyama
    • Keisuke Miyazawa
    • Akio Tomoda
  • View Affiliations

  • Published online on: March 1, 2010     https://doi.org/10.3892/ijo_00000540
  • Pages: 641-650
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Abstract

2-Aminophenoxazine-3-one (Phx-3)-induced apoptosis was investigated. Phx-3 suppressed the viability of human lung adenocarcinoma cell line A549 and induced cellular apoptosis 6 h after treatment. Prior to these events, intracellular pH (pHi) was rapidly decreased from pH 7.65 to 7.10 within 30 min when A549 cells were treated with 7 µM Phx-3. This intracellular acidification continued for 3 h in the cells. Augmented production of reactive oxygen species (ROS) was obseved 1 h after treatment of A549 cells with 7 µM Phx-3, and cell cycle arrest at G1 was indicated 3 h after treatment. The translocation of NF-κB from the cytosol to the nucleus was clearly indicated 1 h after the administration of Phx-3 to A549 cells, while it was significantly suppressed when Nac, a scavenger of ROS, was added to the cells with Phx-3. The Phx-3-induced apoptosis in A549 cells was significantly suppressed when Nac was administered to the cells. These results suggest that a decrease of pHi, caused by depolarization of the mitochondria, may trigger the dysfunction of mitochondria causing ROS production; therefore, both the translocation of NF-κB from the cytoplasm to the nucleus and apoptosis induction were promoted in A549 cells. Microscopic examination of the cellular localization of Phx-3 in A549 cells revealed that Phx-3 was mainly localized in the cytoplasm and the mitochondria, but not in the nucleus. The present results indicate that Phx-3 might be a strong anticancer drug against lung cancer, which is intractable to chemotherapy, by causing various early events, including the decrease of pHi and ROS production, and finally inducing cellular apoptosis.

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March 2010
Volume 36 Issue 3

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

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Spandidos Publications style
Zheng C, Che X, Akiyama S, Miyazawa K and Tomoda A: 2-Aminophenoxazine-3-one induces cellular apoptosis by causing rapid intracellular acidification and generating reactive oxygen species in human lung adenocarcinoma cells. Int J Oncol 36: 641-650, 2010
APA
Zheng, C., Che, X., Akiyama, S., Miyazawa, K., & Tomoda, A. (2010). 2-Aminophenoxazine-3-one induces cellular apoptosis by causing rapid intracellular acidification and generating reactive oxygen species in human lung adenocarcinoma cells. International Journal of Oncology, 36, 641-650. https://doi.org/10.3892/ijo_00000540
MLA
Zheng, C., Che, X., Akiyama, S., Miyazawa, K., Tomoda, A."2-Aminophenoxazine-3-one induces cellular apoptosis by causing rapid intracellular acidification and generating reactive oxygen species in human lung adenocarcinoma cells". International Journal of Oncology 36.3 (2010): 641-650.
Chicago
Zheng, C., Che, X., Akiyama, S., Miyazawa, K., Tomoda, A."2-Aminophenoxazine-3-one induces cellular apoptosis by causing rapid intracellular acidification and generating reactive oxygen species in human lung adenocarcinoma cells". International Journal of Oncology 36, no. 3 (2010): 641-650. https://doi.org/10.3892/ijo_00000540