College of Medicine, Inha University, 3-ga, Sinheung-dong, Jung-gu, Incheon 400-712, Republic of Korea.
Cancer Lett. 2013 May 1;331(2):250-61. doi: 10.1016/j.canlet.2013.01.007. Epub 2013 Jan 20.
The RAF/MEK/ERK and PI3K/AKT pathways are highly implicated in the development of pancreatic cancer. The principal objective of this study was to assess the synergic effect between Sorafenib (a RAF inhibitor) and HS-173 (a novel PI3K inhibitor) to gain insight into novel therapeutic strategies for treating pancreatic cancer. We first investigated the cytotoxic effect of co-treatment with Sorafenib and HS-173 using the Calcusyn program. Combined treatment of the two drugs synergistically inhibited the viability of Panc-1 cells (combination index<1). Concomitantly, the co-treatment induced G2/M arrest and increased apoptosis with the loss of mitochondrial membrane potential. Apoptosis resulting from the co-treatment was accompanied by increased levels of cleaved caspase-3 and PARP as well as greater numbers of TUNEL-positive apoptotic cells compared to treatment with either drug alone. Furthermore, combined treatment with these drugs decreased the expression of HIF-1α and VEGF which play an important role in angiogenesis. This anti-angiogenic effect was confirmed by the suppressed tube formation of VEGF-induced human umbilical vein endothelial cells and inhibition of blood vessel formation in a Matrigel plug assay in mice. Taken together, our study demonstrates that combined treatment with Sorafenib and HS-173 has a synergistic anti-cancer effect on pancreatic cancer cells, indicating that simultaneously targeting the RAF/MEK and PI3K/AKT pathways can induce a synergistic inhibitory effect on pancreatic cancers in which both pathways are activated. Based on the observations from our study, we suggest that the combined administration of these two drugs may be considered to be a new therapeutic regimen for treating pancreatic cancer.
RAF/MEK/ERK 和 PI3K/AKT 通路在胰腺癌的发生发展中高度相关。本研究的主要目的是评估索拉非尼（RAF 抑制剂）和 HS-173（一种新型 PI3K 抑制剂）联合应用的协同作用，以深入了解治疗胰腺癌的新策略。我们首先使用 Calcusyn 程序研究了索拉非尼和 HS-173 联合治疗的细胞毒性作用。两种药物联合治疗协同抑制 Panc-1 细胞活力（组合指数<1）。同时，联合治疗诱导 G2/M 期阻滞并增加线粒体膜电位丧失导致的细胞凋亡。与单独用药相比，联合用药诱导的细胞凋亡伴随着 cleaved caspase-3 和 PARP 的增加以及 TUNEL 阳性凋亡细胞的增加。此外，联合使用这两种药物可降低 HIF-1α和 VEGF 的表达，它们在血管生成中起重要作用。这种抗血管生成作用通过抑制 VEGF 诱导的人脐静脉内皮细胞的管形成和在小鼠 Matrigel plugs 实验中抑制血管形成得到证实。总之，我们的研究表明，索拉非尼和 HS-173 联合治疗对胰腺癌具有协同抗癌作用，表明同时靶向 RAF/MEK 和 PI3K/AKT 通路可对两条通路均激活的胰腺癌产生协同抑制作用。基于我们的研究结果，我们建议联合使用这两种药物可能被考虑作为治疗胰腺癌的新治疗方案。
