Vaticanol C, a phytoalexin, induces apoptosis of leukemia and cancer cells by modulating expression of multiple sphingolipid metabolic enzymes
Vaticanol C, a phytoalexin, induces apoptosis of leukemia and cancer cells by modulating expression of multiple sphingolipid metabolic enzymes
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DOI：
10.18999/nagjms.82.2.261
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发表时间：
2020-05-01
影响因子：
0.9
通讯作者：
Murate, Takashi
中科院分区：
文献类型：
--
作者：
Inoue, Chisato;Sobue, Sayaka;Murate, Takashi
白藜芦醇（RSV）因其多效性作用最近引起了人们的浓厚兴趣。它具有广泛的促进健康的作用。除了促进健康的作用外，RSV 还具有抗癌活性。但需要非生理浓度才能发挥抗癌作用，且其体内生物利用度较低。 '所以。植物化学物质的临床应用需要替代候选物，以较低的浓度诱导所需的效果并增加生物利用度。我们之前报道过，在 12 种 RSV 衍生物中，梵蒂冈醇 C (VTC)（一种 RSV 四聚体）的 IC50 较低（Ito T. 等，2003）。然而，所涉及的确切机制仍有待确定。在这里，我们筛选了一个内部化学库，其中包含从二聚体到八聚体的 RSV 构建模块，以了解对几种白血病和癌细胞系及其抗癌药物耐药亚系的细胞毒性作用。化合物之中。 VTC 表现出最高的细胞毒性，其部分被 caspase 3 抑制剂 Z-VAD-FMK 抑制。 VTC 通过转录或转录后机制降低鞘氨醇激酶 1、鞘氨醇激酶 2 和葡萄糖神经酰胺合成酶的表达，并增加细胞神经酰胺/二氢神经酰胺并减少 1-磷酸鞘氨醇 (S1P)。 VTC 诱导的鞘脂变阻器调节（神经酰胺/S1P 的比率）被认为与细胞凋亡有关。事实上，添加外源 SIP 可以显着调节 VTC 细胞毒性。 SPHK1、SPHK2 的组合。 GCS 化学抑制剂诱导鞘脂变阻器调节、细胞生长抑制和与 VTC 类似的细胞毒性。这些结果表明鞘脂代谢参与了 VTC 诱导的细胞毒性，并表明 VTC 是一个有前途的转化研究原型。
Resveratrol (RSV) has recently attracted keen interest because of its pleiotropic effects. It exerts a wide range of health-promoting effects. In addition to health-promoting effects, RSV possesses anti-carcinogenic activity. However, a non-physiological concentration is needed to achieve an anti-cancer effect, and its in vivo bioavailability is low. 'Therefore. the clinical application of phytochemicals requires alternative candidates that induce the desired effects at a lower concentration and with increased bioavailability. We previously reported a low IC50 of vaticanol C (VTC), an RSV tetramer, among 12 RSV derivatives (Ito T. et al, 2003). However, the precise mechanism involved remains to be determined. Here, we screened an in-house chemical library bearing RSV building blocks ranging from dimers to octamers for cytotoxic effects in several leukemia and cancer cell lines and their anti-cancer drug-resistant sublines. Among the compounds. VTC exhibited the highest cytotoxicity, which was partially inhibited by a caspase 3 inhibitor, Z-VAD-FMK. VTC decreased the expression of sphingosine kinase 1, sphingosine kinase 2 and glucosylceramide synthAse by transcriptional or post-transcriptional mechanisms, and increased cellular ceramides/dihydroceramides and decreased sphingosine 1-phosphate (S1P). VTC-induced sphingolipid rheostat modulation (the ratio of ceramide/S1P) is thought to be involved in cellular apoptosis. Indeed, exogenous SIP addition modulated VTC cytotoxicity significantly. A combination of SPHK1, SPHK2. and GCS chemical inhibitors induced sphingolipid rheostat modulation, cell growth suppression, and cytotoxicity similar to that of VTC. These results suggest the involvement of sphingolipid metabolism in VTC-induced cytotoxicity, and indicate VTC is a promising prototype for translational research.