The current 5-year survival rate of pancreatic cancer is about 12%, making it one of the deadliest malignancies. The rapid metastasis, acquired drug resistance, and poor patient prognosis necessitate better therapeutic strategies for pancreatic ductal adenocarcinoma (PDAC). Multiple studies show that combining chemotherapeutics for solid tumors has been successful. Targeting two distinct emerging hallmarks, such as non-mutational epigenetic changes by panobinostat (Pan) and delayed cell cycle progression by abemaciclib (Abe), inhibits pancreatic cancer growth. HDAC and CDK4/6 inhibitors are effective but are prone to drug resistance and failure as single agents. Therefore, we hypothesized that combining Abe and Pan could synergistically and lethally affect PDAC survival and proliferation. Multiple cell-based assays, enzymatic activity experiments, and flow cytometry experiments were performed to determine the effects of Abe, Pan, and their combination on PDAC cells and human dermal fibroblasts. Western blotting was used to determine the expression of cell cycle, epigenetic, and apoptosis markers. The Abe-Pan combination exhibited excellent efficacy and produced synergistic effects, altering the expression of cell cycle proteins and epigenetic markers. Pan, alone and in combination with Abe, caused apoptosis in pancreatic cancer cells. Abe-Pan co-treatment showed relative safety in normal human dermal fibroblasts. Our novel combination treatment of Abe and Pan shows synergistic effects on PDAC cells. The combination induces apoptosis, shows relative safety, and merits further investigation due to its therapeutic potential in the treatment of PDAC.
胰腺癌的5年生存率目前约为12%，是最致命的恶性肿瘤之一。由于其快速转移、获得性耐药及患者预后不良等特点，亟需针对胰腺导管腺癌（PDAC）制定更有效的治疗策略。多项研究表明，联合化疗药物治疗实体肿瘤已取得显著成效。通过靶向两个不同的新兴特征——如帕比司他（Pan）诱导的非突变表观遗传改变和阿贝西利（Abe）介导的细胞周期进程延迟——可有效抑制胰腺癌生长。HDAC抑制剂与CDK4/6抑制剂虽具疗效，但单药使用易产生耐药性和治疗失败。因此，我们提出假设：联合应用Abe与Pan可能对PDAC的存活与增殖产生协同致死效应。通过多种细胞实验、酶活性检测及流式细胞术，我们评估了Abe、Pan及其联合方案对PDAC细胞和人真皮成纤维细胞的影响，并采用蛋白质印迹法检测细胞周期、表观遗传及凋亡标志物的表达。结果显示，Abe-Pan联合方案展现出卓越疗效并产生协同效应，能改变细胞周期蛋白与表观遗传标志物的表达。单独使用Pan或与Abe联用均可诱导胰腺癌细胞凋亡，而Abe-Pan联合处理在正常人真皮成纤维细胞中显示出相对安全性。本研究提出的Abe与Pan新型联合治疗方案对PDAC细胞具有协同作用，能诱导细胞凋亡且安全性良好，鉴于其在PDAC治疗中的潜在价值，值得进一步深入研究。
肿瘤(癌症)患者之家