Gao Hui-Quan, Bu Xiang-Mao, Jiang Wei, Wan Yan-Zhen, Song Wei
Department of Radiotherapy, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China.
Shandong University of Traditional Chinese Medicine, Jinan, China.
Heliyon. 2024 Mar 5;10(5):e27345. doi: 10.1016/j.heliyon.2024.e27345. eCollection 2024 Mar 15.
Compound Taxus capsule, as an antineoplastic Chinese patent drug, has been increasingly applied as an adjunctive treatment for the management of non-small-cell lung cancer (NSCLC) and some other malignancies, but research about its antitumor activity and radiosensitization effect on hepatocellular carcinoma (HCC) cells is very rare.
To investigate the antitumor activity and radiosensitization effect of Compound Taxus on HCC cells and to preliminarily explore the possible molecule mechanisms involved.
Cell viability, cell cycle distribution, apoptosis, DNA damage repair and protein expression levels were detected by CCK-8 assay, flow cytometry, immunofluorescence staining, western blotting analysis and immunohistochemical staining, respectively. The migration and invasion activities and vasculogenic mimicry (VM) formation and angiogenesis were evaluated by tube formation and VM formation assay. Radiation survival curves were obtained from the colony formation assay in human HCC cell lines, Smmc7721 and Bel7402 cells, pretreated with or without Compound Taxus before receiving X-ray irradiation. A Bel7402 tumor-bearing mouse model was established and the radiosensitization effect of Compound Taxus in vivo was evaluated by analyzing tumor volume and tumor weight in different groups receiving different treatments.
Compound Taxus decreased viability, induced G2/M arrest, promoted apoptosis, suppressed migration and invasion, and inhibited VM formation and angiogenesis in Smmc7721 and Bel7402 cells. Furthermore, Compound Taxus inhibited irradiation-induced DNA damage repair, enhanced the radiosensitivity of Smmc7721 and Bel7402 cells and improved the anti-tumor therapeutic efficacy of irradiation in Bel7402 tumor-bearing mice. Radiotherapy in combination with Compound Taxus showed the best tumor inhibition compared to that of Compound Taxus alone or irradiation alone. In addition, Compound Taxus significantly down-regulated NF-κB p65, p-NF-κB p65 and Bcl-2, and up-regulated Bax in vitro and in vivo, yet NF-κB p65 overexpression reversed the proapoptotic effect of Taxus on HCC cells, indicating that the NF-κB signaling pathway might be an important signal mediator in the Compound-Taxus-modulated biological responses.
Our findings suggest that Compound Taxus shows marked antitumor activity and significant radiosensitization effect on HCC cells, making it possible for Compound Taxus to become a promising auxiliary modality for HCC management and a potential radiosensitizer of HCC in the future.
复方红豆杉胶囊作为一种抗肿瘤中药，已越来越多地被用作非小细胞肺癌（NSCLC）和其他一些恶性肿瘤治疗的辅助药物，但关于其对肝癌（HCC）细胞的抗肿瘤活性和放射增敏作用的研究非常罕见。
研究复方红豆杉对肝癌细胞的抗肿瘤活性和放射增敏作用，并初步探讨其可能涉及的分子机制。
分别采用CCK-8法、流式细胞术、免疫荧光染色、蛋白质免疫印迹分析和免疫组织化学染色检测细胞活力、细胞周期分布、凋亡、DNA损伤修复及蛋白质表达水平。通过管腔形成实验和血管生成拟态（VM）形成实验评估迁移、侵袭活性以及VM形成和血管生成。在人肝癌细胞系Smmc7721和Bel7402细胞中，于接受X射线照射前用或不用复方红豆杉预处理，通过集落形成实验获得放射存活曲线。建立Bel7402荷瘤小鼠模型，通过分析不同治疗组的肿瘤体积和肿瘤重量评估复方红豆杉在体内的放射增敏作用。
复方红豆杉降低了Smmc7721和Bel7402细胞的活力，诱导G2/M期阻滞，促进凋亡，抑制迁移和侵袭，并抑制VM形成和血管生成。此外，复方红豆杉抑制辐射诱导的DNA损伤修复，增强Smmc7721和Bel7402细胞的放射敏感性，并提高Bel7402荷瘤小鼠辐射的抗肿瘤治疗效果。与单独使用复方红豆杉或单独放疗相比，放疗联合复方红豆杉显示出最佳的肿瘤抑制效果。此外，复方红豆杉在体外和体内均显著下调NF-κB p65、p-NF-κB p65和Bcl-2，并上调Bax，但NF-κB p65过表达逆转了红豆杉对肝癌细胞的促凋亡作用，表明NF-κB信号通路可能是复方红豆杉调节生物学反应的重要信号介质。
我们的研究结果表明，复方红豆杉对肝癌细胞具有显著的抗肿瘤活性和放射增敏作用，使其有可能成为未来肝癌治疗中一种有前景的辅助治疗方式和潜在的肝癌放射增敏剂。
