Abstract：
OBJECTIVE: Liver cancer is the fourth leading cause of cancer-related death worldwide, with hepatocellular carcinoma (HCC) being the most common type of primary liver cancer. APG-1252 is a small molecule inhibitor targeting Bcl-2 and Bcl-xl. However, its anti-tumor effects in HCC, alone or in combination with Cabozantinib, have not been extensively studied.
METHODS: Approach: TCGA database analysis was used to analysis the gene expression levels of Bcl-2 and Bcl-xl in HCC tissues. Western blot was employed to detect the protein expression levels. And the inhibitory effects of APG-1252 and Cabozantinib on the proliferation of HCC cell lines was detected by CCK-8. The effect on the migration and invasion of HCC cells was verified by transwell assay. Huh7 xenograft model in nude mice was used to investigate the combination antitumor effect in vivo.
RESULTS: Our study demonstrated that APG-1252 monotherapy inhibited the proliferation and migration ability of HCC cells, and induced HCC cells apoptosis. The combination of APG-1252 and Cabozantinib showed significant synergistic antitumor effects. Furthermore, the in vivo experiment demonstrated that the combination therapy exerted a synergistic effect in delaying tumor growth, notably downregulating MEK/ERK phosphorylation levels. In terms of mechanism, Cabozantinib treatment caused an increase in the phosphorylation levels of CREB and Bcl-xl proteins, while the combination with APG-1252 mitigated this effect, thereby enhanced the antitumor effect of Cabozantinib.
CONCLUSIONS: Our findings suggest that APG-1252 in combination with Cabozantinib offers a more effective treatment strategy for HCC patients, warranting further clinical investigation.
METHODS: Approach: TCGA database analysis was used to analysis the gene expression levels of Bcl-2 and Bcl-xl in HCC tissues. Western blot was employed to detect the protein expression levels. And the inhibitory effects of APG-1252 and Cabozantinib on the proliferation of HCC cell lines was detected by CCK-8. The effect on the migration and invasion of HCC cells was verified by transwell assay. Huh7 xenograft model in nude mice was used to investigate the combination antitumor effect in vivo.
RESULTS: Our study demonstrated that APG-1252 monotherapy inhibited the proliferation and migration ability of HCC cells, and induced HCC cells apoptosis. The combination of APG-1252 and Cabozantinib showed significant synergistic antitumor effects. Furthermore, the in vivo experiment demonstrated that the combination therapy exerted a synergistic effect in delaying tumor growth, notably downregulating MEK/ERK phosphorylation levels. In terms of mechanism, Cabozantinib treatment caused an increase in the phosphorylation levels of CREB and Bcl-xl proteins, while the combination with APG-1252 mitigated this effect, thereby enhanced the antitumor effect of Cabozantinib.
CONCLUSIONS: Our findings suggest that APG-1252 in combination with Cabozantinib offers a more effective treatment strategy for HCC patients, warranting further clinical investigation.
摘要：
目的：肝癌是全球癌症相关死亡的第四大原因，肝细胞癌（HCC）是最常见的原发性肝癌类型。APG-1252是靶向Bcl-2和Bcl-xl的小分子抑制剂。然而,其在肝癌中的抗肿瘤作用，单独或与卡博替尼联合使用，没有被广泛研究。
方法：方法：使用TCGA数据库分析来分析HCC组织中Bcl-2和Bcl-xl的基因表达水平。蛋白质印迹用于检测蛋白质表达水平。CCK-8检测APG-1252和卡博替尼对肝癌细胞株增殖的抑制作用。通过transwell实验验证了对HCC细胞迁移和侵袭的影响。使用裸鼠中的Huh7异种移植模型来研究体内联合抗肿瘤作用。
结果：我们的研究表明，APG-1252单药治疗抑制肝癌细胞的增殖和迁移能力，诱导肝癌细胞凋亡。APG-1252和卡博替尼的组合显示出显著的协同抗肿瘤作用。此外，体内实验表明，联合治疗在延缓肿瘤生长方面发挥了协同作用，显著下调MEK/ERK磷酸化水平。在机制方面,卡博替尼治疗导致CREB和Bcl-xl蛋白的磷酸化水平增加，虽然与APG-1252的组合减轻了这种影响，从而增强卡博替尼的抗肿瘤作用。
结论：我们的研究结果表明，APG-1252与卡博替尼联合为HCC患者提供了更有效的治疗策略。保证进一步的临床研究。
方法：方法：使用TCGA数据库分析来分析HCC组织中Bcl-2和Bcl-xl的基因表达水平。蛋白质印迹用于检测蛋白质表达水平。CCK-8检测APG-1252和卡博替尼对肝癌细胞株增殖的抑制作用。通过transwell实验验证了对HCC细胞迁移和侵袭的影响。使用裸鼠中的Huh7异种移植模型来研究体内联合抗肿瘤作用。
结果：我们的研究表明，APG-1252单药治疗抑制肝癌细胞的增殖和迁移能力，诱导肝癌细胞凋亡。APG-1252和卡博替尼的组合显示出显著的协同抗肿瘤作用。此外，体内实验表明，联合治疗在延缓肿瘤生长方面发挥了协同作用，显著下调MEK/ERK磷酸化水平。在机制方面,卡博替尼治疗导致CREB和Bcl-xl蛋白的磷酸化水平增加，虽然与APG-1252的组合减轻了这种影响，从而增强卡博替尼的抗肿瘤作用。
结论：我们的研究结果表明，APG-1252与卡博替尼联合为HCC患者提供了更有效的治疗策略。保证进一步的临床研究。
