Tobío Araceli, Alfonso Amparo, Madera-Salcedo Iris, Botana Luis M, Blank Ulrich
INSERM UMRS 1149, Paris, France.
Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, Campus Universitario, Lugo, Spain.
PLoS One. 2016 Dec 14;11(12):e0167572. doi: 10.1371/journal.pone.0167572. eCollection 2016.
Yessotoxins (YTXs) are a group of marine toxins produced by the dinoflagellates Protoceratium reticulatum, Lingulodinium polyedrum and Gonyaulax spinifera. They may have medical interest due to their potential role as anti-allergic but also anti-cancer compounds. However, their biological activities remain poorly characterized. Here, we show that the small molecular compound YTX causes a slight but significant reduction of the ability of mast cells to degranulate. Strikingly, further examination revealed that YTX had a marked and selective cytotoxicity for the RBL-2H3 mast cell line inducing apoptosis, while primary bone marrow derived mast cells were highly resistant. In addition, YTX exhibited strong cytotoxicity against the human B-chronic lymphocytic leukaemia cell line MEC1 and the murine melanoma cell line B16F10. To analyse the potential role of YTX as an anti-cancer drug in vivo we used the well-established B16F10 melanoma preclinical mouse model. Our results demonstrate that a few local application of YTX around established tumours dramatically diminished tumour growth in the absence of any significant toxicity as determined by the absence of weight loss and haematological alterations. Our data support that YTX may have a minor role as an anti-allergic drug, but reveals an important potential for its use as an anti-cancer drug.
岩沙海葵毒素(YTXs)是由网状原角藻、多边舌甲藻和具刺膝沟藻等甲藻产生的一组海洋毒素。由于它们作为抗过敏和抗癌化合物的潜在作用,可能具有医学研究价值。然而,它们的生物学活性仍未得到充分表征。在此,我们表明小分子化合物YTX会使肥大细胞脱颗粒能力略有但显著降低。令人惊讶的是,进一步研究发现YTX对RBL-2H3肥大细胞系具有显著且选择性的细胞毒性,可诱导其凋亡,而原代骨髓来源的肥大细胞则具有高度抗性。此外,YTX对人B慢性淋巴细胞白血病细胞系MEC1和小鼠黑色素瘤细胞系B16F10表现出强烈的细胞毒性。为了分析YTX作为体内抗癌药物的潜在作用,我们使用了成熟的B16F10黑色素瘤临床前小鼠模型。我们的结果表明,在已形成的肿瘤周围局部应用少量YTX可显著减少肿瘤生长,且未出现任何明显毒性,这可通过体重减轻和血液学改变的缺失来确定。我们的数据支持YTX可能作为抗过敏药物作用较小,但揭示了其作为抗癌药物的重要潜在价值。