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索拉非尼治疗及对鞘脂代谢通路的调控对体外肝癌细胞增殖和活力的影响。

Sorafenib Treatment and Modulation of the Sphingolipid Pathway Affect Proliferation and Viability of Hepatocellular Carcinoma In Vitro.

机构信息

Medizinische Klinik 1, University Hospital, Goethe University Frankfurt am Main, 60590 Frankfurt, Germany.

Institut für Allgemeine Pharmakologie und Toxikologie, University Hospital, Goethe University Frankfurt am Main, 60590 Frankfurt, Germany.

出版信息

Int J Mol Sci. 2020 Mar 31;21(7):2409. doi: 10.3390/ijms21072409.

DOI:10.3390/ijms21072409
PMID:32244391
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7177910/
Abstract

Hepatocellular carcinoma (HCC) shows a remarkable heterogeneity and is recognized as a chemoresistant tumor with dismal prognosis. In previous studies, we observed significant alterations in the serum sphingolipids of patients with HCC. This study aimed to investigate the in vitro effects of sorafenib, which is the most widely used systemic HCC medication, on the sphingolipid pathway as well as the effects of inhibiting the sphingolipid pathway in HCC. Huh7.5 and HepG2 cells were stimulated with sorafenib, and inhibitors of the sphingolipid pathway and cell proliferation, viability, and concentrations of bioactive metabolites were assessed. We observed a significant downregulation of cell proliferation and viability and a simultaneous upregulation of dihydroceramides upon sorafenib stimulation. Interestingly, fumonisin B1 (FB1) and the general sphingosine kinase inhibitor SKI II were able to inhibit cell proliferation more prominently in HepG2 and Huh7.5 cells, whereas there were no consistent effects on the formation of dihydroceramides, thus implying an involvement of distinct metabolic pathways. In conclusion, our study demonstrates a significant downregulation of HCC proliferation upon sorafenib, FB1, and SKI II treatment, whereas it seems they exert antiproliferative effects independently from sphingolipids. Certainly, further data would be required to elucidate the potential of FB1 and SKI II as putative novel therapeutic targets in HCC.

摘要

肝细胞癌 (HCC) 表现出显著的异质性，被认为是一种对化疗药物有耐药性的肿瘤，预后不良。在之前的研究中，我们观察到 HCC 患者血清神经鞘脂的明显改变。本研究旨在探讨索拉非尼（目前最广泛用于治疗 HCC 的全身性药物）对神经鞘脂通路的体外影响，以及抑制 HCC 中神经鞘脂通路的作用。用索拉非尼刺激 Huh7.5 和 HepG2 细胞，评估神经鞘脂通路抑制剂以及细胞增殖、活力和生物活性代谢物浓度的影响。我们观察到索拉非尼刺激后细胞增殖和活力显著下调，同时二氢神经酰胺上调。有趣的是，FB1 和通用鞘氨醇激酶抑制剂 SKI II 能够更显著地抑制 HepG2 和 Huh7.5 细胞的增殖，而对二氢神经酰胺的形成没有一致的影响，这表明存在不同的代谢途径。总之，本研究表明索拉非尼、FB1 和 SKI II 处理可显著下调 HCC 增殖，而它们似乎独立于神经鞘脂发挥抗增殖作用。当然，还需要进一步的数据来阐明 FB1 和 SKI II 作为 HCC 潜在新治疗靶点的潜力。

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