Walden Daniel, Kunnimalaiyaan Selvi, Sokolowski Kevin, Clark T Gamblin, Kunnimalaiyaan Muthusamy
Division of Surgical Oncology, Department of Surgery, MCW Cancer Center, Translational and Biomedical Research Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Oncotarget. 2017 Sep 30;8(50):88069-88078. doi: 10.18632/oncotarget.21422. eCollection 2017 Oct 20.
Cholangiocarcinoma remains the second most prevalent hepatic neoplasm in the United States with a 5-year survival rate of less than 10%. Currently, no systemic therapy has demonstrated efficacy. Therefore, an urgent need for the identification of molecularly targeted compound(s) remains. The Notch signaling pathway has been shown to be dysregulated in cholangiocarcinoma, exhibiting hyperactivity while also possibly mediating chemotherapeutic resistance. We analyzed the effects of xanthohumol, a prenylated chalcone, on cholangiocarcinoma proliferation utilizing human cholangiocarcinoma cell lines CCLP1, SG-231 and CC-SW-1 while gaining insight into the associated mechanism. Xanthohumol potently reduced cellular proliferation, colony formation, and cell confluency in all three cell lines. Xanthohumol induced cell cycle arrest as well as apoptosis through the reduction of cell cycle regulatory proteins as well as an increase in pro-apoptotic markers (cleaved poly ADP ribose polymerase, cleaved caspase-3) and a decrease in anti-apoptotic markers (X-linked inhibitor of apoptosis and survivin). At the molecular level, xanthohumol reduced Notch1 and AKT expression in a step-wise and time-dependent fashion, with Notch1 reductions preceding AKT. Additionally, xanthohumol reduced cholangiocarcinoma growth in both CCLP-1 and SG-231 derived mice xenografts. In summary, we show that xanthohumol significantly reduced cholangiocarcinoma growth through the Notch1/AKT signaling axis. Furthermore, known pharmacokinetics and bioavailability of XN supports continued development of treatment for cholangiocarcinoma.
胆管癌仍然是美国第二常见的肝脏肿瘤，其5年生存率低于10%。目前，尚无全身治疗显示出疗效。因此，迫切需要鉴定分子靶向化合物。Notch信号通路已被证明在胆管癌中失调，表现为活性过高，同时也可能介导化疗耐药性。我们利用人胆管癌细胞系CCLP1、SG-231和CC-SW-1分析了异戊烯基查耳酮黄腐酚对胆管癌增殖的影响，并深入了解其相关机制。黄腐酚在所有三种细胞系中均能有效降低细胞增殖、集落形成和细胞汇合度。黄腐酚通过减少细胞周期调节蛋白以及增加促凋亡标志物（裂解的聚ADP核糖聚合酶、裂解的半胱天冬酶-3）和减少抗凋亡标志物（X连锁凋亡抑制蛋白和生存素）诱导细胞周期停滞和凋亡。在分子水平上，黄腐酚以逐步和时间依赖性方式降低Notch1和AKT表达，Notch1的降低先于AKT。此外，黄腐酚在CCLP-1和SG-231衍生的小鼠异种移植瘤中均能抑制胆管癌生长。总之，我们表明黄腐酚通过Notch1/AKT信号轴显著降低胆管癌生长。此外，已知的黄腐酚药代动力学和生物利用度支持继续开发胆管癌治疗方法。
