title: Combination of arsenic trioxide and BCNU synergistically triggers redox-mediated autophagic cell death in human solid tumors.
abstract: Arsenic trioxide (As(2)O(3)) is an effective treatment for relapsed or refractory acute promyelocytic leukemia (APL). After the discovery of As(2)O(3) as a promising treatment for APL, several studies investigated the use of As(2)O(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(2)O(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(2)O(3) exhibits a synergistic interaction with N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU). The synergistic augmentation of the cytotoxicity of As(2)O(3) with BCNU is in part through the autophagic cell death machinery in human solid tumor cells. As(2)O(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(2)O(3) with BCNU. Taken together, this is the first evidence that BCNU could help to extend the therapeutic spectrum of As(2)O(3). These findings will be useful in designing future clinical trials of combination chemotherapy with As(2)O(3) and BCNU, with the potential for broad use against a variety of solid tumors.
authors: National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan. cckuo@nhri.org.tw
authors: Ching-Chuan
authors: CC
authors: Kuo
authors: Tsang-Wu
authors: TW
authors: Liu
authors: Li-Tzong
authors: LT
authors: Chen
authors: Her-Shyong
authors: HS
authors: Shiah
authors: Ching-Ming
authors: CM
authors: Wu
authors: Yen-Ting
authors: YT
authors: Cheng
authors: Wen-Yu
authors: WY
authors: Pan
authors: Jin-Fen
authors: JF
authors: Liu
authors: Kuo-Li
authors: KL
authors: Chen
authors: Yun-Ning
authors: YN
authors: Yang
authors: Shan-Na
authors: SN
authors: Chen
authors: Jang-Yang
authors: JY
authors: Chang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D002330:Carmustine / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005978:Glutathione / Q000378:metabolism; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D010084:Oxidation-Reduction; D010087:Oxides / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D017382:Reactive Oxygen Species; D005980:Glutathione Reductase; D005978:Glutathione; D000077237:Arsenic Trioxide; D002330:Carmustine