Key Laboratory of Endoscopic Technique Research of Zhejiang Province, Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang 310016, China.
Chin Med J (Engl). 2019 Feb 5;132(3):311-318. doi: 10.1097/CM9.0000000000000053.
The clinical trials emerged centromere protein E inhibitor GSK923295 as a promising anticancer drug, but its function in hepatocellular carcinoma (HCC) remain needs to be fully elucidated, especially as chemotherapy after hepatectomy for liver tumors. We aimed to describe anti-HCC activities of GSK923295 and compare its antiproliferative effects on liver regeneration after partial hepatectomy (PH).
All subjects were randomized to treatment with either vehicle or GSK923295. Antitumor activity of GSK923295 was assessed by xenograft growth assays. The C57BL/6 mice were subjected to 70% PH and the proliferation was calculated by liver coefficient, further confirmed by immunohistochemistry. The proliferation and cell cycle analysis of liver cell AML12 and HCC cells LM3, HUH7, and HepG2 were investigated using the cell counting kit-8 assay and Flow Cytometry. The chromosome misalignment and segregation in AML12 cells were visualized by immunofluorescence.
Treatment with GSK923295 induced antiproliferation in HCC cell lines. It also caused delay on HCC tumor growth instead of regression both in a HCC cell line xenograft model and patient-derived tumor xenograft model. With microarray analysis, CENtromere Protein E was gradually increased in mouse liver after PH. Exposure of liver cells to GSK923295 resulted in delay on a cell cycle in mitosis with a phenotype of misaligned chromosomes and chromosomes clustered. In 70% PH mouse model, GSK923295 treatment also remarkably reduced liver regeneration in later stage, in parallel with the mitotic marker phospho-histone H3 elevation.
The anticancer drug GSK923295 causes a significant delay on HCC tumor growth and liver regeneration after PH in later stage.
临床试验表明着丝粒蛋白 E 抑制剂 GSK923295 是一种很有前途的抗癌药物，但它在肝细胞癌（HCC）中的作用仍需充分阐明，尤其是在肿瘤切除术后作为化疗药物。我们旨在描述 GSK923295 的抗 HCC 活性，并比较其对部分肝切除（PH）后肝再生的抗增殖作用。
所有患者均随机接受安慰剂或 GSK923295 治疗。通过异种移植生长测定评估 GSK923295 的抗肿瘤活性。C57BL/6 小鼠接受 70%PH，通过肝系数计算增殖，进一步通过免疫组化证实。通过细胞计数试剂盒-8 测定和流式细胞术研究肝细胞 AML12 和 HCC 细胞 LM3、HUH7 和 HepG2 的增殖和细胞周期分析。通过免疫荧光观察 AML12 细胞中的染色体错位和分离。
GSK923295 治疗诱导 HCC 细胞系增殖抑制。它还导致 HCC 肿瘤生长延迟而不是消退，无论是在 HCC 细胞系异种移植模型还是患者来源的肿瘤异种移植模型中。通过微阵列分析，PH 后小鼠肝脏中的着丝粒蛋白 E 逐渐增加。暴露于 GSK923295 的肝细胞导致有丝分裂周期延迟，表现为染色体错位和染色体聚集。在 70%PH 小鼠模型中，GSK923295 治疗也显著减少了后期的肝再生，与有丝分裂标志物磷酸组蛋白 H3 的升高平行。
抗癌药物 GSK923295 导致 PH 后 HCC 肿瘤生长和后期肝再生明显延迟。
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