Toxicity of trichothecene mycotoxin nivalenol in human leukemia cell line HL60

Abstract

The toxicity of nivalenol (NIV) to the human promyelocyte-derived cell line HL60 is reviewed. NIV cytotoxicity was examined after 24 h treatment, and the inhibitor studies were performed. Cells treated with 3 µg/mL or higher NIV were damaged, and more than half of the cells appeared dead. Regarding cell proliferation, the value of 50 % inhibitory concentration of NIV was 0.16 µg/mL. Apparent DNA ladders were observed, showing that NIV induces apoptosis. Concentrations of NIV-caused morphologic damage are in accordance with DNA fragmentation, indicating that marked NIV-caused morphologic change is due to apoptosis. NIV increased interleukin-8 (IL-8/CXCL8) secretion. Conversely, NIV decreased the secretions of other cytokines monocyte chemotactic protein-1 (MCP-1/CCL2), macrophage inflammatory protein-1α (MIP-1α/CCL3), MIP-1β/CCL4, and regulated upon activation, normal T cell expressed and presumably secreted (RANTES/CCL5) concentration-dependently. That intracellular calcium ion chelator BAPTA-AM mitigated the cytotoxicity of NIV indicates that this effect is dependent on intracellular calcium ion. The results of an intracellular calcium ion modu-lator ryanodine receptor (RyR)1-specific inhibitor dantrolene treatment indicates that RyR1 contributes to NIV-induced toxicity. Stress-activated mitogen-activated protein kinases (SAPKs), c-Jun N-terminal kinases (JNKs) and p38s, occupy the crucial positions in NIV-associated retardation of cell proliferation and IL-8 secretion. Transcription factor nuclear factor-κB (NF-κB) inhibitors reduced NIV's effects, indicating that NF-κB is an important factor for exerting NIV toxicity. Regarding cell proliferation, no protective effect of geldanamycin, a molecular chaperone heat shock protein 90 (Hsp90)-specific inhibitor, was observed. Alternatively, Hsp90 appears to play a role in NIV-associated changes in cytokine secretions.