regorafenib 作用在肝癌细胞中的可逆性。
Reversibility of regorafenib effects in hepatocellular carcinoma cells.
出版信息
Cancer Chemother Pharmacol. 2013 Oct;72(4):869-77. doi: 10.1007/s00280-013-2269-8.
Abstract
PURPOSE
Multikinase growth inhibitors inhibit their target kinases with varying potency. Patients often require lower doses or therapy breaks due to drug toxicities. To evaluate the effects of drug withdrawal on hepatocellular carcinoma cells after incubation with growth-inhibitory concentrations of regorafenib, cell growth, migration and invasion, and signaling were examined.
METHODS
Cell proliferation, motility, and invasion were analyzed by MTT, wound healing, and invasion assays, respectively, and MAPK pathway protein markers were analyzed by Western blot.
RESULTS
After regorafenib removal, cell growth, migration, and invasion recovered. Repeated drug exposure resulted in changes in cell growth patterns. Recovery could be blocked by sub-growth-inhibitory concentrations of either doxorubicin or vitamin K1. Recovery of growth was associated with increased phospho-JNK, phospho-p38, and phospho-STAT3 levels. The recovery of growth, migration, and signaling were blocked by a JNK inhibitor.
CONCLUSIONS
Removal of regorafenib from growth-inhibited cells resulted in a JNK-dependent recovery of growth and migration.
摘要
目的
多激酶生长抑制剂以不同的效力抑制其靶激酶。由于药物毒性，患者通常需要较低的剂量或治疗间歇。为了评估在抑制生长浓度的regorafenib 孵育后药物停药对肝癌细胞的影响，检查了细胞生长、迁移和侵袭以及信号转导。
方法
通过 MTT、划痕愈合和侵袭测定分别分析细胞增殖、迁移和侵袭，并用 Western blot 分析 MAPK 途径蛋白标记物。
结果
regorafenib 去除后，细胞生长、迁移和侵袭恢复。重复药物暴露导致细胞生长模式发生变化。亚生长抑制浓度的阿霉素或维生素 K1 可阻断恢复。生长的恢复与磷酸化-JNK、磷酸化-p38 和磷酸化-STAT3 水平的增加有关。生长、迁移和信号转导的恢复被 JNK 抑制剂阻断。
结论
从生长受抑制的细胞中去除regorafenib 导致 JNK 依赖性生长和迁移恢复。
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