Canine hemangiosarcoma (HSA) is a commonly occurring aggressive tumor stemming from the vascular endothelial cells and is considered to be a good model for a similar disease in humans, called angiosarcoma. In this study, we reviewed drug libraries to identify new signal transduction inhibitors that can suppress the cell growth of canine HSA in vitro. We observed that tenovin-6, a sirtuin (SIRT) inhibitor, inhibited cell proliferation and induced cell death in three canine HSA cell lines (JuB4, Re12, and Ud6). These effects were induced through G1 cell cycle arrest and caspase-3 activation. Although tenovin-6 is known as an inhibitor of SIRT1 and SIRT2, knockout (KO) of genes encoding SIRT1 and/or SIRT2 had no apparent impact on cell proliferation in canine HSA. In addition, tenovin-6 showed cell growth inhibition in SIRT KO cells, as well as parental cells. These results indicated the cytotoxicity of tenovin-6 was a SIRT-independent event. Instead, we found that tenovin-6 inhibited autophagy flux in canine HSA cells, as evidenced by the suppression of lysosomal proteolysis. These results suggested that tenovin-6 induces cell growth suppression in canine HSA cells by impairing the lysosomal function. Therefore, tenovin-6 could be used in a new therapeutic strategy to treat canine HSA.

中文翻译：

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Tenovin-6诱导不依赖SIRT的细胞生长并阻断犬血管瘤肉瘤细胞系中的自噬通量。

犬血管肉瘤（HSA）是一种常见的侵袭性肿瘤，起源于血管内皮细胞，被认为是人类类似疾病称为血管肉瘤的良好模型。在这项研究中，我们审查了药物库，以识别可以在体外抑制犬HSA细胞生长的新信号转导抑制剂。我们观察到，Sirtuin（SIRT）抑制剂tenovin-6在三种犬HSA细胞系（JuB4，Re12和Ud6）中抑制细胞增殖并诱导细胞死亡。这些作用是通过G1细胞周期停滞和caspase-3激活诱导的。尽管tenovin-6被称为SIRT1和SIRT2的抑制剂，但编码SIRT1和/或SIRT2的基因的敲除（KO）对犬HSA中的细胞增殖没有明显影响。此外，tenovin-6在SIRT KO细胞中显示出细胞生长抑制作用，以及亲代细胞 这些结果表明，tenovin-6的细胞毒性是一种不依赖SIRT的事件。相反，我们发现tenovin-6抑制了犬HSA细胞中的自噬通量，如溶酶体蛋白水解的抑制所证明。这些结果表明，tenovin-6通过破坏溶酶体功能来诱导犬HSA细胞中的细胞生长抑制。因此，tenovin-6可用于治疗犬HSA的新治疗策略。