Sorafenib inhibits ERK1/2 and MCL-1(L) phosphorylation levels resulting in caspase-independent cell death in malignant pleural mesothelioma.
Sorafenib inhibits ERK1/2 and MCL-1(L) phosphorylation levels resulting in caspase-independent cell death in malignant pleural mesothelioma.
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DOI：
10.4161/cbt.8.24.10824
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发表时间：
2009-12
影响因子：
3.6
通讯作者：
El-Deiry WS
中科院分区：
文献类型：
--
作者：
Katz SI;Zhou L;Chao G;Smith CD;Ferrara T;Wang W;Dicker DT;El-Deiry WS
恶性胸膜间皮瘤（MPM）是一种侵袭性，快速进展的恶性肿瘤，没有有效的治疗。我们使用人MPM细胞系MSTO-211 H、M30、REN、H28、H2052和H2452评价了索拉非尼的体外功效和对细胞促存活机制的影响，索拉非尼作为单一疗法以及与天然存在的死亡受体激动剂TRAIL组合的功效。六个MPM系的体外研究证明了对多激酶抑制剂索拉非尼的单药敏感性和对TRAIL的抗性。H28和H2452在体外证实了向索拉非尼中加入TRAIL增强的凋亡。经处理的细胞系显示索拉非尼诱导的AKT快速去磷酸化，随后不久组成性磷酸化ERK 1/2几乎完全去磷酸化。索拉非尼治疗还降低了几种细胞系中B-Raf和mTOR的磷酸化。在索拉非尼处理的3小时内，许多已知的促存活分子被去磷酸化和/或表达下调，包括MCL-1 L、c-FLIPL、存活素和cIAP 1。这些变化和最终的细胞死亡没有引起显著的半胱天冬酶-3活化或PARP裂解，并且用泛半胱天冬酶抑制剂Z-VAD-FMK预处理没有阻断索拉非尼功效，但阻断了TRAIL单一疗法的作用。用Z-VAD-FMK预处理不阻断TRAIL和索拉非尼在H28中的协同作用。总之，索拉非尼单药治疗导致体外促存活机制的广泛抑制，通过主要的半胱天冬酶非依赖性机制导致细胞死亡。联合索拉非尼治疗与TRAIL，可能是有用的，以提供一个更有效的死亡信号，这种协同效应似乎是半胱天冬酶独立的。初步体内数据证明了在携带人肿瘤的异种移植nu/nu小鼠中具有治疗功效的有希望的证据。我们记录了索拉非尼对MPM的单药活性，揭示了索拉非尼对抗凋亡信号传导介质的新作用，并建议索拉非尼加TRAIL的组合作为MPM临床试验的可能疗法。
Malignant pleural mesothelioma (MPM) is an aggressive, rapidly progressive malignancy without effective therapy. We evaluate sorafenib efficacy and impact on the cellular pro-survival machinery in vitro, efficacy of sorafenib as monotherapy and in combination with the naturally occurring death receptor agonist, TRAIL using human MPM cell lines, MSTO-211H, M30, REN, H28, H2052 and H2452. In vitro studies of the six MPM lines demonstrated single agent sensitivity to the multikinase inhibitor sorafenib and resistance to TRAIL. H28 and H2452 demonstrated augmented apoptosis with the addition of TRAIL to sorafenib in vitro. Treated cell lines demonstrated sorafenib-induced rapid dephosphorylation of AKT followed shortly by near complete dephosphorylation of the constitutively phosphorylated ERK1/2. Sorafenib therapy also decreased phosphorylation of B-Raf and mTOR in several cell lines. Within 3 h of sorafenib treatment, a number of known pro-survival molecules were dephosphorylated and/or downregulated in expression including MCL-1L, c-FLIPL, survivin and cIAP 1. These changes and eventual cell death did not elicit significant caspase-3 activation or PARP cleavage and pretreatment with the pan-caspase inhibitor, Z-VAD-FMK, did not block sorafenib efficacy but did block the effect of TRAIL monotherapy. Pre-treatment with Z-VAD-FMK did not block the synergistic effect of TRAIL and sorafenib in H28. In summary, single agent treatment with sorafenib results in widespread inhibition of the pro-survival machinery in vitro leading to cell death via a primarily caspase-independent mechanism. Combining sorafenib therapy with TRAIL, may be useful in order to provide a more efficient death signal and this synergistic effect appears to be caspase-independent. Pilot in vivo data demonstrates promising evidence of therapeutic efficacy in human tumor bearing xenograft nu/nu mice. We document single agent activity of sorafenib against MPM, unravel novel effects of sorafenib on anti-apoptotic signaling mediators, and suggest the combination of sorafenib plus TRAIL as possible therapy for clinical testing in MPM.
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影响因子：
4.3
作者：
Kindler, Hedy Lee
通讯作者：
Kindler, Hedy Lee
影响因子：
5.3
作者：
Ding, Qingqing;He, Xianghuo;Hung, Mien-Chie
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