Toxicity of trichothecene mycotoxin nivalenol in human leukemia cell line HL60

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  • Nagashima Hitoshi
    National Food Research Institute, National Agriculture and Food Research Organization

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  • トリコテセン系マイコトキシンのニバレノールのヒト白血病細胞HL60に対する毒性

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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 BAPTAAM mitigated the cytotoxicity of NIV indicates that this effect is dependent on intracellular calcium ion. The results of an intracellular calcium ion modulator 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.

Journal

  • JSM Mycotoxins

    JSM Mycotoxins 65 (1), 11-17, 2015

    Japanese Society of Mycotoxicology

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