The Effect of Doxorubicin on MEK-ERK Signaling Predicts Its Efficacy in HCC
The Effect of Doxorubicin on MEK-ERK Signaling Predicts Its Efficacy in HCC
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DOI：
10.1016/j.jss.2008.01.029
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发表时间：
2008-12-01
影响因子：
2.2
通讯作者：
Schmidt, C. Max
中科院分区：
文献类型：
--
作者：
Choi, Jennifer;Yip-Schneider, Michele;Schmidt, C. Max
背景。肝细胞癌（HCC）是全球癌症相关死亡的主要原因。历史上，阿霉素（DOX）已被广泛用于治疗不可切除的HCC，但疗效不一。材料和方法。我们假设DOX联合丝裂原活化蛋白激酶激酶-细胞外信号调节激酶（MEK-ERK）靶向治疗可能提供增强的抗癌作用。用DOX和MEK酶抑制剂U0126或PD184161单独或联合治疗人肝癌细胞系（HepG2, Hep3B）。细胞生长、细胞凋亡、ERK表达/MEK活性分别通过增殖试验、DNA片段酶联免疫试验或caspases荧光抑制剂和Western blot检测。DOX （0.01-1 μ M）抑制Hep3B细胞增殖48 ~ 72 h （IC50与0.12 μ M相似）；DOX对HepG2细胞的作用较弱（IC50与0.25 μ M相似）。在DOX处理Hep3B细胞后的早期时间点（30 min）， MEK活性在低剂量下保持不变，在高剂量下下降；24小时后，高剂量的phospho-ERK水平升高。相反，在HepG2细胞中，DOX在早期和晚期时间点引起phospho-ERK水平持续的剂量依赖性增加。MEK抑制剂U0126降低了两种HCC细胞系的磷酸化erk。与DOX相比，HepG2细胞比Hep3B细胞对U0126更敏感。DOX与U0126（或PD184161）联合使用对HepG2细胞的增殖有更大的抑制作用，但对Hep3B细胞没有抑制作用。这种作用可能部分是由细胞凋亡增强介导的。DOX对早期和晚期诱导MEK活性的影响可以预测其在HCC中的化疗反应。此外，这种效应也可能决定MEK抑制剂联合治疗的效用。(C) 2008爱思唯尔公司版权所有。
Background. Hepatocellular cancer (HCC) is a leading cause of cancer-related death worldwide. Historically, doxorubicin (DOX) has been widely used against unresectable HCC with variable response rates.Materials and methods. We hypothesized that DOX combined with mitogen-activated protein kinase kinase-extracellular signal-regulated kinase (MEK-ERK) targeted therapy may provide enhanced anticancer effects. Human HCC cell lines (HepG2, Hep3B) were treated with DOX and MEK enzyme inhibitors, U0126 or PD184161, alone or in combination. Growth, apoptosis, and ERK expression/MEK activity were respectively determined by proliferation assay, DNA fragmentation enzyme-linked immunoassay or fluorochrome inhibitor of caspases, and Western blot.Results. DOX (0.01-1 mu M) decreased cell proliferation in Hep3B cells (IC50 similar to 0.12 mu M) at 48 to 72 h; DOX was less effective in HepG2 cells (IC50 similar to 0.25 mu M). At early time points (30 min) after DOX treatment of Hep3B cells, MEK activity was unchanged at low doses and decreased at higher doses; after 24 h, phospho-ERK levels increased at higher doses. Contrarily, in HepG2 cells, DOX caused a sustained, dose-dependent increase in phospho-ERK levels at early and late time points. The MEK inhibitor U0126 decreased phospho-ERK in both HCC lines. In contrast to DOX, HepG2 cells were more sensitive than Hep3B cells to U0126. The combination of DOX with U0126 (or PD184161) resulted in greater inhibition of proliferation in HepG2 but not in Hep3B cells. This effect may be mediated in part by enhanced apoptosis.Conclusions. The effect of DOX on early and late induction of MEK activity predicts its chemotherapeutic response in HCC. Furthermore, this effect may also determine the utility of MEK inhibitor combination treatment. (C) 2008 Elsevier Inc. All rights reserved.