Center for Neuroscience, National Sun Yat-Sen University, Kaohsiung, Taiwan.
Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.
Cancer Med. 2018 Jun;7(6):2567-2580. doi: 10.1002/cam4.1487. Epub 2018 Apr 23.
Epirubicin is a chemotherapy agent for hepatocellular carcinoma (HCC). However, the outcome of HCC patients receiving epirubicin remains unsatisfactory. Moreover, our previous study indicated that celecoxib suppresses HCC progression and liver cancer stemness. This study evaluated the potential of celecoxib to serve as a complementary therapy during epirubicin treatment. Cell proliferation, apoptosis, invasiveness, and anchorage-independent growth were analyzed in hepatoma cells. Therapeutic efficacy was validated in rat orthotopic Novikoff hepatoma. After animal sacrifice, the antitumor mechanism of celecoxib and epirubicin combined therapy was investigated by histological analysis. Celecoxib enhanced the cytotoxic activity of epirubicin in HCC cells by promoting apoptosis. Besides, celecoxib potentiated the antineoplastic function of epirubicin in inhibiting the invasiveness and anchorage-independent growth of HCC cells. Ultrasound monitoring showed that combined therapy was more potent than either therapy alone in perturbing HCC progression. Consistently, the size and weight of dissected HCC tissues from rats receiving combined therapy were smallest among all groups. HCC treated with combined therapy exhibited the highest prevalence of apoptotic cells, which was accompanied by reduced proliferating and angiogenic activities in tumor tissues. Moreover, the expression levels of cancer stemness markers (CD44 and CD133) and drug transporter MDR-1 were significantly diminished in rats receiving combined therapy. Besides, celecoxib treatment increased the infiltration of cytotoxic T lymphocytes (CTLs) and reduced the number of regulatory T cells (Tregs), tumor-associated macrophages (TAMs), and the expression of immune checkpoint PD-L1 in HCC tissues during epirubicin therapy. Celecoxib augmented the therapeutic efficacy while modulated cancer stemness and antitumor immunity. Thus, celecoxib may serve as complementary therapy to improve the outcome of patients with advanced HCC during epirubicin treatment.
表阿霉素是一种用于治疗肝细胞癌（HCC）的化疗药物。然而，接受表阿霉素治疗的 HCC 患者的预后仍不理想。此外，我们之前的研究表明塞来昔布可抑制 HCC 进展和肝癌干细胞特性。本研究评估了塞来昔布作为表阿霉素治疗辅助疗法的潜力。在肝癌细胞中分析细胞增殖、凋亡、侵袭和无锚定生长。在大鼠原位 Novikoff 肝癌中验证了治疗效果。动物处死后，通过组织学分析研究了塞来昔布和表阿霉素联合治疗的抗肿瘤机制。塞来昔布通过促进细胞凋亡增强了 HCC 细胞中表阿霉素的细胞毒性作用。此外，塞来昔布增强了表阿霉素抑制 HCC 细胞侵袭和无锚定生长的抗肿瘤功能。超声监测显示，联合治疗比单独治疗更能干扰 HCC 进展。一致地，接受联合治疗的大鼠解剖 HCC 组织的大小和重量在所有组中最小。联合治疗的 HCC 表现出最高比例的凋亡细胞，这伴随着肿瘤组织中增殖和血管生成活性的降低。此外，联合治疗的大鼠中癌症干细胞标志物（CD44 和 CD133）和药物转运蛋白 MDR-1 的表达水平显著降低。此外，塞来昔布治疗增加了细胞毒性 T 淋巴细胞（CTLs）的浸润，并减少了调节性 T 细胞（Tregs）、肿瘤相关巨噬细胞（TAMs）的数量和 HCC 组织中免疫检查点 PD-L1 的表达，在表阿霉素治疗期间。塞来昔布增强了治疗效果，同时调节了癌症干细胞特性和抗肿瘤免疫。因此，塞来昔布可能作为辅助疗法，改善接受表阿霉素治疗的晚期 HCC 患者的预后。
