Institute of Microbiology, School of Life Sciences, Lanzhou University, Lanzhou 730000, China.
Gansu High Throughput Screening and Creation Center for Health Products, School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
Eur J Pharm Sci. 2021 Dec 1;167:106017. doi: 10.1016/j.ejps.2021.106017. Epub 2021 Sep 21.
HM-3-HSA is an antitumor fusion protein which improved the pharmacokinetics of HM-3. Previous studies reported that HM-3-HSA enhanced antitumor activity of HM-3 in melanoma cells. However, the efficacy and the mechanism of HM-3-HSA in hepatocellular carcinoma, especially its effect on tumor angiogenesis, have not been elucidated. Herein, we showed that HM-3-HSA significantly inhibited the H22 and SMMC-7721 tumor xenografts growth and tumor angiogenesis in vivo, indicating the antitumor activity exerted by HM-3-HSA was closely corrected with its potency on tumor angiogenesis. To investigate the anti-angiogenic mechanism, we evaluated the efficacy of HM-3-HSA in HUVECs in vitro. The results showed that multiple steps of tumor angiogenesis, including endothelial cell proliferation, migration, invasion and tube formation, were substantially inhibited by HM-3-HSA. Mechanism investigations revealed that HM-3-HSA could bind HUVECs via integrin αvβ3 and α5β1 and inhibited phosphorylation of the downstream protein kinases including FAK, Src and PI3 K. Our study was the first to report the activity of HM-3-HSA against hepatocellular carcinoma and tumor angiogenesis as well as the underlying mechanism by which HM-3-HSA to exert its anti-angiogenic activity.
HM-3-HSA 是一种抗肿瘤融合蛋白，可改善 HM-3 的药代动力学。先前的研究报道 HM-3-HSA 增强了 HM-3 在黑色素瘤细胞中的抗肿瘤活性。然而，HM-3-HSA 在肝细胞癌中的疗效和机制，特别是其对肿瘤血管生成的影响，尚未阐明。在此，我们表明 HM-3-HSA 显著抑制了 H22 和 SMMC-7721 肿瘤异种移植物的生长和体内肿瘤血管生成，表明 HM-3-HSA 的抗肿瘤活性与其对肿瘤血管生成的效力密切相关。为了研究抗血管生成机制，我们评估了 HM-3-HSA 在体外 HUVEC 中的功效。结果表明，HM-3-HSA 可显著抑制血管生成的多个步骤，包括内皮细胞增殖、迁移、侵袭和管形成。机制研究表明，HM-3-HSA 可通过整合素 αvβ3 和 α5β1 与 HUVEC 结合，并抑制下游蛋白激酶如 FAK、Src 和 PI3K 的磷酸化。我们的研究首次报道了 HM-3-HSA 对肝细胞癌和肿瘤血管生成的活性以及 HM-3-HSA 发挥抗血管生成活性的潜在机制。
