Clinical application of
anticancer agents has been often hampered by toxicity against normal cells, so the achievement of their
cancer-specific action is still one of the major challenges to be addressed. Previously, we reported that
arsenic trioxide (
As2O3) could be a promising new
drug against not only
leukemia but also solid
tumors. The cytotoxicity of
As2O3 occurred through the generation of
reactive oxygen species (ROS), thus inhibiting radical scavenging systems would enhance the therapeutic efficacy of
As2O3 provided that normal cells were relatively resistant to such a measure. Here, we report that the combination
therapy of
As2O3 with L-
buthionine-sulfoximine (BSO), which inhibits a critical step in
glutathione synthesis, effectively enhanced in vitro growth inhibition effect of
As2O3 on all 11 investigated cell lines arising from prostate, breast, lung, colon, cervix, bladder, and
kidney cancers, compared with
As2O3 treatment alone. Furthermore, this combination enhanced cytotoxicity to cell lines from
prostate cancer with less toxicity to those from normal prostate. In vitro cytotoxic assay using ROS-related compounds demonstrated that
hydrogen peroxide (H2O2) is a major cytotoxic mediator among ROS molecules. Biochemical analysis showed that combined use of
As2O3 and BSO blocked H2O2-scavenging systems including
glutathione,
catalase, and
glutathione peroxidase, and that the degree of this blockade was well correlated with intracellular ROS levels and sensitivity to this treatment. Finally, the effectiveness of the combination
therapy of
As2O3 with BSO was demonstrated with an orthotopic model of
prostate cancer metastasis. We propose that the combination
therapy of
As2O3 with BSO is a valid means of blockade of H2O2-scavenging system, and that the combination of a ROS-generating agent with an inhibitor of major scavenging systems is effective in terms of both efficacy and selectivity. Furthermore, because the effective doses of both compounds are within clinically achievable range, this report will lead to immediate benefit for the development of a new
cancer therapy.