Department of Medical Oncology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Int J Cancer. 2010 Dec 15;127(12):2949-58. doi: 10.1002/ijc.25498.
The multikinase 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). As few nontoxic agents have activity against HCC growth, we evaluated the activity of sorafenib and VKs, both independently and together on the growth of HCC cells in vitro and in vivo. 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 of VK1 plus sorafenib induced apoptosis on FACS, TUNEL staining and caspase activation. Phospho-extracellular signal-regulated kinase (ERK) levels were decreased as was myeloid cell leukemia sequence 1 (Mcl-1), an ERK target. Sorafenib alone inhibited growth of transplantable HCC in vivo. At subeffective sorafenib doses in vivo, addition of VK1 caused major tumor regression, with decreased phospho-ERK and Mcl-1 staining. Thus, combination of VK1 plus sorafenib strongly induced growth inhibition and apoptosis in rodent and human HCC and inhibited the RAF/mitogen-activated protein kinase kinase/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. As both agents are available for human use, the combination has potential for improving sorafenib effects in HCC.
多激酶抑制剂索拉非尼是第一个对人肝细胞癌（HCC）显示活性的口服药物。已经表明，几种药物包括索拉非尼以及天然存在的 K 维生素（VK）在内，可诱导 HCC 细胞凋亡。由于很少有非毒性药物对 HCC 生长具有活性，因此我们评估了索拉非尼和 VK 单独以及联合在体外和体内对 HCC 细胞生长的活性。我们发现，当 VK 与索拉非尼联合使用时，抑制生长所需的索拉非尼浓度大大降低。相反，VK 在几种 HCC 细胞系中增强了索拉非尼对生长抑制的作用。使用维生素 K1、K2 和 K5，可在单独使用任何一种药物都无效的剂量下抑制 VK 加索拉非尼的生长。VK1 加索拉非尼联合诱导 FACS、TUNEL 染色和 caspase 激活的细胞凋亡。磷酸化细胞外信号调节激酶（ERK）水平降低，ERK 靶标髓样细胞白血病序列 1（Mcl-1）也是如此。索拉非尼单独抑制体内移植性 HCC 的生长。在体内亚效剂量的索拉非尼下，添加 VK1 会导致肿瘤主要消退，磷酸化 ERK 和 Mcl-1 染色减少。因此，VK1 加索拉非尼联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/丝裂原激活蛋白激酶激酶/ERK 途径。VK1 单独激活 PKA，一种抑制 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用于人类，因此该联合疗法有可能改善索拉非尼在 HCC 中的作用。
