Division of Gastroenterology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, 59 Yatap-ro, Bundang-gu, Seongnam, 13496, Republic of Korea.
Institute for Clinical Research, CHA Bundang Medical Center, CHA University, School of Medicine, Seongnam, Republic of Korea.
Cancer Chemother Pharmacol. 2019 Oct;84(4):809-817. doi: 10.1007/s00280-019-03918-y. Epub 2019 Aug 5.
PURPOSE: Sorafenib has been the only first systemic drug that improves survival of patients with advanced hepatocellular carcinoma (HCC). However, because the response rate of sorafenib is relatively low, novel therapeutic strategies are needed to improve survival in patients with HCC. This study investigated the effect of CMG002 alone and in combination with sorafenib on HCC in vitro and vivo. METHODS: The effect of a newly developed dual PI3K/mTOR inhibitor, CMG002, on the proliferation of Huh-7 and HepG2 HCC cells was investigated using the MTT assay. Western blotting was performed to assess phosphorylation of the key enzymes in the Ras/Raf/MAPK and PI3K/AKT/mTOR pathways. HepG2 cells were inoculated into mice, which were treated with vehicle, sorafenib, CMG002, and their combinations. Tumor cell proliferation and tumor angiogenesis were evaluated by immunohistochemical analysis of Ki-67 and CD31, respectively. Tumor cell apoptosis was detected by the terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Levels of key enzymes in the Ras/Raf/MAPK and PI3K/AKT/mTOR pathways were evaluated by western blot analysis. RESULTS: The combination of sorafenib and CMG002 additively inhibited Huh-7 and HepG2 cell proliferation compared to single-agent treatment. Sorafenib and CMG002 as single agents differentially inhibited or activated key enzymes in the Ras/Raf/MAPK and PI3K/AKT/mTOR pathways. The combination of sorafenib and CMG002 inhibited all key enzymes in the two pathways. Treatment with CMG002 for 4 weeks alone and in combination with sorafenib strongly inhibited tumor growth. CMG002 inhibited HCC cell proliferation, induced apoptosis, and decreased tumor angiogenesis. Furthermore, these effects were enhanced when CMG002 was combined with sorafenib. CONCLUSIONS: The combination of CMG002 and sorafenib significantly inhibited HCC cell proliferation and tumorigenesis by inhibiting the Ras/Raf/MAPK and PI3K/AKT/mTOR pathways. These findings suggest that CMG002 to be a potential novel candidate treatment for HCC.
目的：索拉非尼是唯一一种能够改善晚期肝细胞癌（HCC）患者生存的一线系统药物。然而，由于索拉非尼的反应率相对较低，因此需要新的治疗策略来提高 HCC 患者的生存率。本研究探讨了 CMG002 单独及联合索拉非尼对 HCC 的体内外作用。
方法：采用 MTT 法检测新型双 PI3K/mTOR 抑制剂 CMG002 对 Huh-7 和 HepG2 HCC 细胞增殖的影响。采用 Western blot 法检测 Ras/Raf/MAPK 和 PI3K/AKT/mTOR 通路关键酶的磷酸化。将 HepG2 细胞接种于小鼠体内，分别给予载体、索拉非尼、CMG002 及其联合治疗。通过 Ki-67 和 CD31 的免疫组化分析分别评估肿瘤细胞增殖和肿瘤血管生成。采用末端脱氧核苷酸转移酶 dUTP 缺口末端标记法检测肿瘤细胞凋亡。采用 Western blot 法检测 Ras/Raf/MAPK 和 PI3K/AKT/mTOR 通路关键酶的水平。
结果：与单药治疗相比，索拉非尼和 CMG002 联合用药可显著抑制 Huh-7 和 HepG2 细胞的增殖。索拉非尼和 CMG002 单药治疗可不同程度地抑制或激活 Ras/Raf/MAPK 和 PI3K/AKT/mTOR 通路中的关键酶。索拉非尼和 CMG002 联合治疗可抑制两条通路中的所有关键酶。CMG002 单药治疗或与索拉非尼联合治疗 4 周可显著抑制肿瘤生长。CMG002 可抑制 HCC 细胞增殖，诱导细胞凋亡，减少肿瘤血管生成。此外，CMG002 与索拉非尼联合使用时，这些作用增强。
结论：CMG002 联合索拉非尼可通过抑制 Ras/Raf/MAPK 和 PI3K/AKT/mTOR 通路显著抑制 HCC 细胞增殖和肿瘤发生。这些发现提示 CMG002 可能成为 HCC 的一种潜在新型治疗药物。
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