Combination of arsenic trioxide and BCNU synergistically triggers redox-mediated autophagic cell death in human solid tumors

Ching Chuan Kuo, Tsang Wu, Li Tzong Chen, Her Shyong Shiah, Ching Ming Wu, Yen Ting Cheng, Wen Yu Pan, Jin Fen Liu, Kuo Li Chen, Yun Ning Yang, Shan Na Chen, Jang Yang Chang

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13 Citations (Scopus)

Abstract

Arsenic trioxide (As 2O 3) is an effective treatment for relapsed or refractory acute promyelocytic leukemia (APL). After the discovery of As 2O 3 as a promising treatment for APL, several studies investigated the use of As 2O 3 as a single agent in the treatment of solid tumors; however, its therapeutic efficacy is limited. Thus, the systematic study of the combination of As 2O 3 with other clinically used chemotherapeutic drugs to improve its therapeutic efficacy in treating human solid tumors is merited. In this study, we demonstrate for the first time, using isobologram analysis, that As 2O 3 exhibits a synergistic interaction with N,N′-bis(2-chloroethyl)-N-nitrosourea (BCNU). The synergistic augmentation of the cytotoxicity of As 2O 3 with BCNU is in part through the autophagic cell death machinery in human solid tumor cells. As 2O 3 and BCNU in combination produce enhanced cytotoxicity via the depletion of reduced glutathione (GSH) and augmentation of reaction oxygen species (ROS) production. Further analysis indicated that the extension of GSH depletion by this combined regimen occurs through the inhibition of the catalytic activity of glutathione reductase. Blocking ROS production with antioxidants or ROS scavengers effectively inhibits cell death and autophagy formation, indicating that redox-mediated autophagic cell death involves the synergism of As 2O 3 with BCNU. Taken together, this is the first evidence that BCNU could help to extend the therapeutic spectrum of As 2O 3. These findings will be useful in designing future clinical trials of combination chemotherapy with As 2O 3 and BCNU, with the potential for broad use against a variety of solid tumors.

Original languageEnglish
Pages (from-to)2195-2209
Number of pages15
JournalFree Radical Biology and Medicine
Volume51
Issue number12
DOIs
Publication statusPublished - Dec 15 2011
Externally publishedYes

Keywords

  • Arsenic trioxide
  • Autophagy
  • BCNU
  • Cancer therapy
  • Free radicals
  • Redox
  • Synergism

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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  • Cite this

    Kuo, C. C., Wu, T., Chen, L. T., Shiah, H. S., Wu, C. M., Cheng, Y. T., Pan, W. Y., Liu, J. F., Chen, K. L., Yang, Y. N., Chen, S. N., & Chang, J. Y. (2011). Combination of arsenic trioxide and BCNU synergistically triggers redox-mediated autophagic cell death in human solid tumors. Free Radical Biology and Medicine, 51(12), 2195-2209. https://doi.org/10.1016/j.freeradbiomed.2011.09.023