Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Oncol Rep. 2018 Apr;39(4):1573-1582. doi: 10.3892/or.2018.6281. Epub 2018 Feb 26.
Pancreatic cancer is the fourth leading cause of cancer-associated mortality worldwide, with an overall 5-year survival rate <8%. We studied the therapeutic effect of itraconazole (ITZ), a commonly used broad-spectrum anti-fungal agent, in the treatment of pancreatic cancer, and to reveal the underlying anticancer mechanisms. Effects of ITZ on cell proliferation, apoptosis, invasion and migration were observed by MTT assays and colony formation assays, flow cytometry, wound scratch assays and transwell assays, respectively. Western blotting and immunofluorescence were performed to investigate the effect of ITZ on the epithelial to mesenchymal transition (EMT) of pancreatic cancer cells. Recombinant transforming growth factor-β (TGF-β) and TGF-β neutralizing antibody were used to study the effect of ITZ on the TGF-β/SMAD2/3 signaling. Transgenic engineered mice which harboring the spontaneous pancreatic cancer was applied to investigate the therapeutic role of ITZ in vivo. We report that ITZ inhibited the viability and induced apoptosis of pancreatic cancer cells. Furthermore, ITZ suppressed the invasion and migration of pancreatic cancer cells. We found that ITZ treatment was efficient in suppressing EMT and that the effect of ITZ was partially mediated by impaired TGF-β/SMAD2/3 signaling. The role of TGF-β/SMAD2/3 signaling in mediating the effect of ITZ was confirmed based on the results that recombinant TGF-β induced, but the TGF-β neutralizing antibody inhibited EMT as well as the invasion and migration of pancreatic cancer cells. Also, the anticancer effect of ITZ could be partially reversed by recombinant TGF-β. Furthermore, treatment with ITZ suppressed growth of tumor in vivo. Taken together, we suggest that ITZ may potentially serve as a new chemotherapeutic agent for the treatment of pancreatic cancer.
胰腺癌是全球癌症相关死亡的第四大主要原因，总体 5 年生存率<8%。我们研究了伊曲康唑（ITZ），一种常用的广谱抗真菌药物，在胰腺癌治疗中的治疗效果，并揭示了潜在的抗癌机制。通过 MTT 测定、集落形成测定、流式细胞术、划痕实验和 Transwell 实验分别观察 ITZ 对细胞增殖、凋亡、侵袭和迁移的影响。Western blot 和免疫荧光实验用于研究 ITZ 对胰腺癌细胞上皮间质转化（EMT）的影响。使用重组转化生长因子-β（TGF-β）和 TGF-β 中和抗体研究 ITZ 对 TGF-β/SMAD2/3 信号的影响。应用携带自发性胰腺癌的转基因工程小鼠研究 ITZ 在体内的治疗作用。我们报告 ITZ 抑制了胰腺癌细胞的活力并诱导了其凋亡。此外，ITZ 抑制了胰腺癌细胞的侵袭和迁移。我们发现 ITZ 治疗能有效抑制 EMT，并且 ITZ 的作用部分是通过受损的 TGF-β/SMAD2/3 信号介导的。基于重组 TGF-β 诱导、而 TGF-β 中和抗体抑制 EMT 以及胰腺癌细胞的侵袭和迁移的结果，证实了 TGF-β/SMAD2/3 信号在介导 ITZ 作用中的作用。此外，重组 TGF-β 部分逆转了 ITZ 的抗癌作用。此外，ITZ 治疗抑制了体内肿瘤的生长。综上所述，我们认为 ITZ 可能是治疗胰腺癌的一种新的化疗药物。
