Department of Abdominal Ultrasonography, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
Neoplasma. 2021 Sep;68(5):924-937. doi: 10.4149/neo_2021_210113N57. Epub 2021 May 17.
Homoharringtonine (HHT), was first isolated from the bark of Cephalotaxus harringtonia (Knight ex J. Forbes) K. Koch and Cephalotaxus fortunei Hook trees. The bark extract is used to treat leukemia and in recent years has also been used in traditional Chinese medicine (TCM) to treat solid tumors. However, the inhibitory mechanism of HHT in the progression of hepatocellular carcinoma (HCC) is rarely studied. We aimed to evaluate the antitumor efficacy of HHT on HCC in vitro and in vivo and elucidate the underlying molecular mechanism(s). HCC cell lines, including HCCLM3, HepG2, and Huh7, were used to evaluate the antitumor efficacy of HHT in vitro. Cytotoxicity and proliferative ability were evaluated by MTT and colony formation assays. Cell cycle progression and apoptosis in HHT-treated HCC cells were evaluated by flow cytometry. To determine the migration and invasion abilities of HCC cells, wound-healing and Transwell assays were used. Finally, western blot analysis was used to reveal the proteins involved. We also established a xenograft nude mouse model for in vivo assessments of the preclinical efficacy of HHT, mainly using hematoxylin and eosin staining, immunohistochemistry, ultrasound imaging (USI), and magnetic resonance imaging (MRI). HHT suppressed the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of HCC cells, and induced cell cycle arrest at the G2 phase and apoptosis. In the HCC xenograft model, HHT showed an obvious tumor-suppressive effect. Surprisingly, Slug expression was also decreased by HHT via the PI3K/AKT/GSK3β signaling pathway at least partially suppressed the growth of HCC via the PI3K/AKT/GSK3β/Slug signaling pathway.
高三尖杉酯碱（HHT）最初是从三尖杉科的粗榧（Knight ex J. Forbes）K. Koch 和中国粗榧 Cephalotaxus fortunei Hook 的树皮中分离出来的。树皮提取物用于治疗白血病，近年来也用于中医治疗实体瘤。然而，HHT 抑制肝细胞癌（HCC）进展的机制很少被研究。我们旨在评估 HHT 在体外和体内对 HCC 的抗肿瘤疗效，并阐明潜在的分子机制。我们使用 HCCLM3、HepG2 和 Huh7 等肝癌细胞系评估 HHT 在体外的抗肿瘤疗效。通过 MTT 和集落形成实验评估细胞毒性和增殖能力。通过流式细胞术评估 HHT 处理的 HCC 细胞中细胞周期进展和细胞凋亡。为了确定 HCC 细胞的迁移和侵袭能力，我们使用划痕愈合和 Transwell 测定。最后，使用 Western blot 分析揭示涉及的蛋白质。我们还建立了裸鼠异种移植模型，用于体内评估 HHT 的临床前疗效，主要使用苏木精和伊红染色、免疫组织化学、超声成像（USI）和磁共振成像（MRI）。HHT 抑制 HCC 细胞的增殖、迁移、侵袭和上皮间质转化（EMT），并诱导细胞周期停滞在 G2 期和细胞凋亡。在 HCC 异种移植模型中，HHT 表现出明显的肿瘤抑制作用。令人惊讶的是，HHT 通过 PI3K/AKT/GSK3β 信号通路至少部分降低 Slug 表达，通过 PI3K/AKT/GSK3β/Slug 信号通路抑制 HCC 的生长。
