Effective treatment of advanced solid tumors by the combination of arsenic trioxide and L-buthionine-sulfoximine

Abstract

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 (As 2 O 3 ) could be a promising new drug against not only leukemia but also solid tumors. The cytotoxicity of As 2 O 3 occurred through the generation of reactive oxygen species (ROS), thus inhibiting radical scavenging systems would enhance the therapeutic efficacy of As 2 O 3 provided that normal cells were relatively resistant to such a measure. Here, we report that the combination therapy of As 2 O 3 with L-buthionine-sulfoximine (BSO), which inhibits a critical step in glutathione synthesis, effectively enhanced in vitro growth inhibition effect of As 2 O 3 on all 11 investigated cell lines arising from prostate, breast, lung, colon, cervix, bladder, and kidney cancers, compared with As 2 O 3 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 ROSrelated compounds demonstrated that hydrogen peroxide (H 2 O 2 ) is a major cytotoxic mediator among ROS molecules. Biochemical analysis showed that combined use of As 2 O 3 and BSO blocked H 2 O 2 -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 As 2 O 3 with BSO was demonstrated with an orthotopic model of prostate cancer metastasis. We propose that the combination therapy of As 2 O 3 with BSO is a valid means of blockade of H 2 O 2 -scavenging system, and that the combination of a ROSgenerating 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.

A novel arsenical has antitumor activity toward As2O3-resistant and MRP1/ABCC1-overexpressing cell lines

“…As shown in Figure 4c, NAC protects NB4 cells from either As 2 O 3 or darinaparsin-induced cell death. BSO depletes GSH by inhibiting g-glutamyl-cysteine synthetase, a rate-limiting enzyme of GSH synthesis 31,32 and sensitizes a wide variety of malignant cells to As 2 O 3 toxicity. 13 Although GSH depletion by nontoxic doses of BSO could significantly increase As 2 O 3 sensitivity, the cytotoxicity of darinaparsin was not modified by decreased intracellular GSH levels (Figure 4d).…”

Structure–activity relationships for organometallic osmium arene phenylazopyridine complexes with potent anticancer activity

“…L-BSO is on clinical trial for combination treatment with Melphalan, 47 and increases the cytotoxicity of a number of therapeutic agents, including cisplatin, especially towards resistant cancer cell lines. 48,49 The only reported exception in which the L-BSO can block the cytotoxicity of a drug appears to be taxol. 32 Our report is apparently only the second in which a blocking of anticancer activity by L-BSO has been observed.…”

Redox status of thioredoxin-1 (TRX1) determines the sensitivity of human liver carcinoma cells (HepG2) to arsenic trioxide-induced cell death

“…These changes in mitochondrial physiology would result in cytochrome c (cyto c) release and subsequent activation www.cell-research.com | Cell Research Changhai Tian et al 459 npg of the apoptotic cascade. It is known that the intracellular redox system modulates both the anti-proliferative and pro-apoptotic effects of As 2 O 3 , and that the content of cellular GSH is negatively related to the sensitivity of tumor cells to As 2 O 3 [14][15][16]. The redox state in mammalian cells is primarily a consequence of the precise balance between the level of ROS and endogenous thiol buffers present in the cell, particularly, GSH and thioredoxin (TRX), which protect cells from oxidative damage [17].…”