Division of Surgical Oncology, Department of Surgery, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
J Exp Clin Cancer Res. 2013 Mar 6;32(1):12. doi: 10.1186/1756-9966-32-12.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human malignancies and tends to be relatively resistant to conventional therapies. Activated Ras oncogene mutations are found in up to 90% of PDAC, leading to activation of the Ras/Raf/MEK/ERK signaling pathway. Sorafenib is a multikinase inhibitor of the Ras/Raf/MEK/ERK pathway and of tumor angiogenesis. Endothelial monocyte activating polypeptide II (EMAP) enhances gemcitabine effects in PDAC. Antitumor activity of sorafenib was evaluated in combination with gemcitabine (Gem) and the antiangiogenic agent EMAP in experimental PDAC.
Cell proliferation and protein expression were analyzed by WST-1 assay and Western blotting. Animal survival studies were performed in murine PDAC xenografts.
Sorafenib decreased phospho-MEK, phospho-ERK1/2, phospho-p70S6K and phospho-4EBP-1 expression in PDAC cells. Sorafenib inhibited in vitro proliferation of all four PDAC cell lines tested. Additive effects on cell proliferation inhibition were observed in the gemcitabine-sorafenib combination in PDAC cells, and in combinations of sorafenib or EMAP with gemcitabine in endothelial (HUVEC) and fibroblast (WI-38) cells. Sorafenib, alone or in combination with gemcitabine and EMAP, induced apoptosis in HUVECs and WI-38 cells as observed via increased expression of cleaved poly (ADP-ribose) polymerase-1 (PARP-1) and caspase-3 proteins. Compared to controls (median survival: 22 days), animal survival increased after Gem therapy (29 days) but not in sorafenib (23 days) or EMAP therapy alone (25 days). Further increases in survival occurred in combination therapy groups Gem+sorafenib (30 days, p=0.004), Gem+EMAP (33 days, p=0.002), and Gem+sorafenib+EMAP (36 days, p=0.004), but not after the sorafenib+EMAP combination (24 days).
These findings demonstrate that the addition of a polymechanistic antiangiogenic agent such as EMAP can enhance the combination treatment effects of sorafenib and cytotoxic PDAC therapy.
胰腺导管腺癌 (PDAC) 是人类最具侵袭性的恶性肿瘤之一，通常对常规治疗相对耐药。高达 90%的 PDAC 存在激活的 Ras 癌基因突变，导致 Ras/Raf/MEK/ERK 信号通路的激活。索拉非尼是 Ras/Raf/MEK/ERK 通路和肿瘤血管生成的多激酶抑制剂。内皮单核细胞激活肽 II (EMAP) 增强 PDAC 中吉西他滨的作用。本研究评价索拉非尼联合吉西他滨 (Gem) 和抗血管生成剂 EMAP 在实验性 PDAC 中的抗肿瘤活性。
通过 WST-1 测定和 Western blot 分析细胞增殖和蛋白表达。在小鼠 PDAC 异种移植模型中进行动物生存研究。
索拉非尼降低了 PDAC 细胞中磷酸化 MEK、磷酸化 ERK1/2、磷酸化 p70S6K 和磷酸化 4EBP-1 的表达。索拉非尼抑制了所有四种 PDAC 细胞系的体外增殖。在 PDAC 细胞中，吉西他滨-索拉非尼联合用药具有相加的细胞增殖抑制作用，索拉非尼或 EMAP 与吉西他滨联合用药在内皮 (HUVEC) 和成纤维细胞 (WI-38) 中也具有相加作用。索拉非尼单独或与吉西他滨和 EMAP 联合用药诱导 HUVEC 和 WI-38 细胞凋亡，表现为 cleaved poly (ADP-ribose) polymerase-1 (PARP-1) 和 caspase-3 蛋白表达增加。与对照组（中位生存时间：22 天）相比，吉西他滨治疗后动物生存时间延长（29 天），但索拉非尼（23 天）或 EMAP 治疗组（25 天）无改善。吉西他滨联合索拉非尼（30 天，p=0.004）、吉西他滨联合 EMAP（33 天，p=0.002）和吉西他滨联合索拉非尼联合 EMAP（36 天，p=0.004）联合治疗组的生存时间进一步延长，但索拉非尼联合 EMAP 组（24 天）无改善。
这些发现表明，添加多机制抗血管生成剂（如 EMAP）可增强索拉非尼和细胞毒性 PDAC 治疗的联合治疗效果。
