Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China.
Sci Rep. 2020 Feb 19;10(1):2964. doi: 10.1038/s41598-020-59746-1.
Transcatheter arterial embolization (TAE) plays an important role in clinical liver tumor therapy. However, hypoxia after TAE limit the medium-long term efficacy of TAE. Thus, in our study, we explored the treatment effect and mechanism of combining transcatheter arterial embolization with adopted iodized oil containing Apatinib on suppressing tumor growth and metastasis. We simulated the changing of tumor microenvironment before and after TAE both in vitro and in vivo models. The anti-angiogenic effect of Apatinib was explored by bioassays in human umbilical vein endothelial cells (HUVECs), including cell migration, invasion and apoptosis, tube formation, and wound healing. Further experiments showed that Apatinib inhibited tumor microangiogenesis to achieve the aims of inhibiting tumor growth and recurrence by means of down-regulating the phosphorylation of the RAF-mek-erk, PI3K-akt and P38MAPK pathways. The antitumor growth and anti-angiogenic effect of Apatinib was further validated by the animal experiment. Taken together, we concluded that Apatinib inhibits the angiogenesis and growth of liver cancer by down-regulating the PI3K-akt, RAF-mek-erk and P38MAPK pathways, and has a stronger inhibitory effect in hypoxic environments. Combining TAE with adopted iodized oil containing Apatinib has a stronger inhibitory effect in VX2 liver tumor growth and metastasis, which suggesting such combinations may provide a new target and strategy for interventional therapy of liver cancer.
经导管动脉栓塞术(TAE)在临床肝脏肿瘤治疗中发挥着重要作用。然而,TAE 后的缺氧会限制 TAE 的中远期疗效。因此,在本研究中,我们探索了经导管动脉栓塞术与含有阿帕替尼的碘化油联合应用在抑制肿瘤生长和转移方面的治疗效果和机制。我们在体外和体内模型中模拟了 TAE 前后肿瘤微环境的变化。通过人脐静脉内皮细胞(HUVEC)中的生物测定法探索了阿帕替尼的抗血管生成作用,包括细胞迁移、侵袭和凋亡、管形成和伤口愈合。进一步的实验表明,阿帕替尼通过下调 RAF-mek-erk、PI3K-akt 和 P38MAPK 通路的磷酸化来抑制肿瘤微血管生成,从而达到抑制肿瘤生长和复发的目的。动物实验进一步验证了阿帕替尼的抗肿瘤生长和抗血管生成作用。综上所述,我们得出结论,阿帕替尼通过下调 PI3K-akt、RAF-mek-erk 和 P38MAPK 通路抑制肝癌的血管生成和生长,并且在缺氧环境下具有更强的抑制作用。将 TAE 与含有阿帕替尼的碘化油联合应用在 VX2 肝脏肿瘤生长和转移方面具有更强的抑制作用,这表明这种联合应用可能为肝癌的介入治疗提供新的靶点和策略。