Catfish egg lectin affects influx and efflux rates of sunitinib in human cervical carcinoma HeLa cells
Catfish egg lectin affects influx and efflux rates of sunitinib in human cervical carcinoma HeLa cells
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DOI：
10.1093/glycob/cwaa029
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发表时间：
2020-10-01
期刊：
影响因子：
4.3
通讯作者：
Hosono, Masahiro
中科院分区：
文献类型：
--
作者：
Sugawara, Shigeki;Takayanagi, Madoka;Hosono, Masahiro
新的治疗方案旨在减少多靶点酪氨酸激酶抑制剂舒尼替尼的剂量，因为舒尼替尼根据其剂量引起许多不良反应。据报道，鲶卵凝集素（SAL）通过与细胞表面的神经酰胺三己糖（Gb 3）结合，可增强碘化丙啶和多柔比星在伯基特淋巴瘤Raji细胞中的掺入。本研究的目的是检查SAL是否增强舒尼替尼在表达Gb 3的HeLa细胞中的细胞毒性作用。虽然SAL处理延迟了细胞的生长并增强了碘化丙啶的摄取，但没有观察到伴随膜塌陷的细胞死亡。与单独使用相比，当与SAL组合治疗时，舒尼替尼治疗的HeLa细胞的活力显著降低。在SAL处理的细胞中，舒尼替尼摄取显著增加30分钟，并且这种增加几乎完全被添加SAL的半抗原糖L-鼠李糖而不是D-葡萄糖所消除。从培养基中去除SU后，SAL处理的细胞中的细胞内舒尼替尼水平高于未处理的细胞24小时，这在Gb 3缺陷的HeLa细胞中没有观察到。此外，我们观察到SAL促进了溶酶体样结构的形成，该结构在HeLa细胞中呈LAMP 1阳性但不呈酸性，可以捕获舒尼替尼。有趣的是，在另一种Gb 3阳性Raji细胞中未观察到SAL诱导的HeLa细胞空泡化。我们的研究结果表明，SAL/Gb 3相互作用促进舒尼替尼摄取和抑制舒尼替尼排泄，舒尼替尼有效地发挥细胞毒性对HeLa细胞。
New treatment protocols are aiming to reduce the dose of the multitargeted tyrosine kinase inhibitor sunitinib, as sunitinib elicits many adverse effects depending on its dosage. Silurus asotus egg lectin (SAL) has been reported to enhance the incorporation of propidium iodide as well as doxorubicin into Burkitt's lymphoma Raji cells through binding to globotriaosylceramide (Gb3) on the cell surface. The objective of this study was to examine whether SAL enhances the cytotoxic effect of sunitinib in Gb3-expressing HeLa cells. Although the treatment with SAL delayed the cell growth and enhanced the propidium iodide uptake, cell death accompanied by membrane collapse was not observed. The viability of sunitinib-treated HeLa cells was significantly reduced when the treatment occurred in combination with SAL compared to their separate usage. Sunitinib uptake significantly increased for 30 min in SAL-treated cells, and this increment was almost completely abolished by the addition of L-rhamnose, a hapten sugar of SAL, but not by D-glucose. After removal of SU from the medium, the intracellular sunitinib level in SAL-treated cells was higher than in untreated cells for 24 h, which was not observed in Gb3-deficient HeLa cells. Furthermore, we observed that SAL promoted the formation of lysosome-like structures, which are LAMP1 positive but not acidic in HeLa cells, which can trap sunitinib. Interestingly, SAL-induced vacuolation in HeLa cells was not observed in another Gb3 positive Raji cells. Our findings suggest that SAL/Gb3 interaction promoted sunitinib uptake and suppressed sunitinib excretion and that sunitinib efficiently exerted cytotoxicity against HeLa cells.