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.