Abstract

Aims: We investigated whether bortezomib synergizes with arsenious acid in killing promyelocytic leukemia HL-60 cells in vitro and in vivo.

Main Methods: Cell culture, MTT assay, Hoechest 33324 staining, flow cytometry assay, determination of DNA fragmentation, immunoblotting analysis, HL60 xenograft mice models and animal experiments.

Key Findings: Bortezomib inhibited proliferation of HL-60 cells in a time- and dose-dependent manner. 20nM bortezomib enhanced the cytotoxic effect of arsenious acid. Consistent with the results in vitro, bortezomib or arsenious acid alone exhibited antitumor activity in HL-60 cell-xenografted mice, whereas combined bortezomib and arsenious acid treatment showed a greater antitumor activity than single treatment. The mice tolerated the drugs with no obvious side-effects. Further mechanistic study found that bortezomib induced cell apoptosis associated with activation of the caspase cascade, including down-regulation of Bcl-2 and cleavage of caspase family members and PARP.

Significance: These results demonstrate that the combination of bortezomib and arsenious acid could be more effective than single agent in inhibiting HL-60 cells viability.

Keywords: Apoptosis, arsenious acid, bortezomib, leukemia, mice xenograft model.