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.

中文翻译：

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鲶鱼卵凝集素影响舒尼替尼在人宫颈癌 HeLa 细胞中的流入和流出率

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会引起许多不良反应。鲇鱼据报道，卵凝集素 (SAL) 可通过与细胞表面的球三酰神经酰胺 (Gb3) 结合来增强碘化丙啶和阿霉素向 Burkitt 淋巴瘤 Raji 细胞的掺入。本研究的目的是检查 SAL 是否增强了舒尼替尼对表达 Gb3 的 HeLa 细胞的细胞毒作用。尽管用 SAL 处理延迟了细胞生长并增强了碘化丙啶的摄取，但未观察到伴随膜塌陷的细胞死亡。与单独使用 SAL 相比，当与 SAL 联合使用时，舒尼替尼处理的 HeLa 细胞的活力显着降低。在 SAL 处理的细胞中，舒尼替尼的吸收在 30 分钟内显着增加，并且通过添加 L-鼠李糖（一种 SAL 的半抗原糖）几乎完全消除了这种增加，但 D-葡萄糖没有。从培养基中去除 SU 后，SAL 处理细胞中的细胞内舒尼替尼水平在 24 小时内高于未处理细胞，这在 Gb3 缺陷型 HeLa 细胞中未观察到。此外，我们观察到 SAL 促进溶酶体样结构的形成，这些结构在 HeLa 细胞中呈 LAMP1 阳性但不呈酸性，可以捕获舒尼替尼。有趣的是，在另一种 Gb3 阳性 Raji 细胞中未观察到 HeLa 细胞中 SAL 诱导的空泡化。我们的研究结果表明，SAL/Gb3 相互作用促进了舒尼替尼的摄取并抑制了舒尼替尼的排泄，并且舒尼替尼有效地对 HeLa 细胞发挥了细胞毒性。我们观察到 SAL 促进了溶酶体样结构的形成，这些结构在 HeLa 细胞中呈 LAMP1 阳性但不呈酸性，可以捕获舒尼替尼。有趣的是，在另一种 Gb3 阳性 Raji 细胞中未观察到 HeLa 细胞中 SAL 诱导的空泡化。我们的研究结果表明，SAL/Gb3 相互作用促进了舒尼替尼的摄取并抑制了舒尼替尼的排泄，并且舒尼替尼有效地对 HeLa 细胞发挥了细胞毒性。我们观察到 SAL 促进了溶酶体样结构的形成，这些结构在 HeLa 细胞中呈 LAMP1 阳性但不呈酸性，可以捕获舒尼替尼。有趣的是，在另一种 Gb3 阳性 Raji 细胞中未观察到 HeLa 细胞中 SAL 诱导的空泡化。我们的研究结果表明，SAL/Gb3 相互作用促进了舒尼替尼的摄取并抑制了舒尼替尼的排泄，并且舒尼替尼有效地对 HeLa 细胞发挥了细胞毒性。