Vitamin K enhancement of sorafenib-mediated HCC cell growth inhibition in vitro and in vivo.
Vitamin K enhancement of sorafenib-mediated HCC cell growth inhibition in vitro and in vivo.
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DOI：
10.1002/ijc.25498
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发表时间：
2010-12-15
影响因子：
6.4
通讯作者：
Carr, Brian I.
中科院分区：
文献类型：
--
作者：
Wei, Gang;Wang, Meifang;Hyslop, Terry;Wang, Ziqiu;Carr, Brian I.
多激酶抑制剂索拉非尼是第一个具有抗人肝细胞癌 (HCC) 活性的口服药物。已证明多种药物（包括索拉非尼）以及天然存在的 K 维生素 (VK) 可在 HCC 中诱导细胞凋亡。由于很少有无毒药物具有抗 HCC 生长的活性，因此我们评估了索拉非尼和维生素 K 的活性，无论是独立的还是共同的对 HCC 细胞体外和体内生长的活性。我们发现，当VK与索拉非尼联合使用时，生长抑制所需的索拉非尼浓度大幅降低。相反，VK 增强了索拉非尼对几种 HCC 细胞系的生长抑制作用。使用维生素 K1、K2 和 K5 时，VK 加索拉非尼的剂量可能会抑制生长，而单独使用任一药物均无效。 VK1 加索拉非尼的组合在 FACS、TUNEL 染色和半胱天冬酶激活上诱导细胞凋亡。磷酸化 ERK 水平下降，ERK 靶标 Mcl-1 水平也下降。索拉非尼单独抑制体内可移植性肝癌的生长。在体内亚有效索拉非尼剂量下，添加 VK1 导致肿瘤主要消退，磷酸化 ERK 和 Mcl-1 染色减少。因此，VK1 与索拉非尼的组合强烈诱导啮齿动物和人类 HCC 的生长抑制和细胞凋亡，并抑制 RAF/MEK/ERK 途径。 VK1 单独激活 PKA，一种抑制性 Raf 磷酸化的介质。因此，每种药物都可以拮抗Raf；索拉非尼作为直接抑制剂，VK1 通过抑制 Raf 磷酸化。由于这两种药物均可供人类使用，因此该组合有可能改善索拉非尼在 HCC 中的疗效。
The multi-kinase inhibitor Sorafenib, is the first oral agent to show activity against human hepatocellular carcinoma (HCC). Apoptosis has been shown to be induced in HCC by several agents, including Sorafenib, as well as by the naturally occurring K vitamins (VKs). Since few non toxic agents have activity against HCC growth, we evaluated the activity of Sorafenib and K vitamins, both independently and together on the growth in vitro and in vivo of HCC cells. We found that when VK was combined with Sorafenib, the concentration of Sorafenib required for growth inhibition was substantially reduced. Conversely, VK enhanced Sorafenib effects in several HCC cell lines on growth inhibition. Growth could be inhibited at doses of VK plus Sorafenib that were ineffective with either agent alone,using vitamins K1, K2 and K5. Combination VK1 plus Sorafenib induced apoptosis on FACS, TUNEL staining and caspase activation. Phospho-ERK levels were decreased, as was Mcl-1, an ERK target. Sorafenib alone inhibited growth of transplantable HCC in vivo. At sub-effective Sorafenib doses in vivo, addition of VK1 caused major tumor regression, with decreased phospho-ERK and Mcl-1 staining. Thus, combination VK1 plus Sorafenib strongly induced growth inhibition and apoptosis in rodent and human HCC and inhibited the RAF/MEK/ERK pathway. VK1 alone activated PKA, a mediator of inhibitory Raf phosphorylation. Thus, each agent can antagonize Raf; Sorafenib as a direct inhibitor and VK1 through inhibitory Raf phosphorylation. Since both agents are available for human use, the combination has potential for improving Sorafenib effects in HCC.
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影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
通讯作者：
Thun, Michael J.
影响因子：
11.5
作者：
Dasmahapatra, Girija;Yerram, Nitin;Grant, Steven
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158.5
作者：
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影响因子：
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作者：
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影响因子：
51.1
作者：
Cheng, Ann-Lii;Kang, Yoon-Koo;Guan, Zhongzhen
通讯作者：
Guan, Zhongzhen