Purpose

Pancreatic ductal adenocarcinoma (PDAC) is the most common and lethal subtype of pancreatic cancer, with a 5-year survival rate of < 3%. Early tumor dissemination, late diagnosis and insensitivity to conventional treatment are the major reasons for its high mortality rate. Members of the vascular endothelial growth factor (VEGF) family are overexpressed in PDAC and play important roles in its malignant progression, suggesting that VEGF-targeted therapies may interrupt the proliferation and motility of PDAC cells. Here, we evaluated the anti-tumor activity of cediranib, a pan-VEGF receptor inhibitor, on PDAC cells.

Methods

Anti-proliferative effects of cediranib were determined using cell proliferation and crystal violet staining assays. Annexin V/PI staining, radiation therapy, and cell migration and invasion assays were carried out to examine the effects of cediranib on apoptosis, radio-sensitivity and cell motility, respectively. Quantitative reverse transcription-PCR (qRT-PCR) and Western blot analyses were applied to elucidate the molecular mechanisms underlying the anti-tumor activity of cediranib.

Results

We found that cediranib decreased PDAC cell proliferation and clonogenic survival and induced apoptotic cell death through inhibition of the anti-apoptotic proteins cIAP1, XIAP, MCL-1 and survivin. Combination with cediranib synergistically increased the sensitivity of PDAC cells to chemotherapeutic agents such as gemcitabine and paclitaxel, and potentiated the effects of radiation therapy on PDAC cell growth inhibition and apoptosis induction. Furthermore, we found that treatment with cediranib impaired PDAC cell migration and invasion via expression reduction of the epithelial-to-mesenchymal transition (EMT) markers ZEB1, N-cadherin and Snail.

Conclusions

Our data indicate that cediranib may exhibit anti-tumor activity in PDAC cells and provide a rationale for further investigation of the potential of VEGF receptor-targeted therapies for the treatment of PDAC.

中文翻译：

---

西地那尼（一种泛血管内皮生长因子受体抑制剂）在胰腺导管腺癌细胞中的抗肿瘤活性。

目的

胰腺导管腺癌（PDAC）是胰腺癌中最常见和致命的亚型，其5年生存率<3％。早期肿瘤扩散，晚期诊断和对常规治疗不敏感是其高死亡率的主要原因。血管内皮生长因子（VEGF）家族的成员在PDAC中过表达，并在其恶性进展中发挥重要作用，这表明以VEGF为靶点的疗法可能会中断PDAC细胞的增殖和运动。在这里，我们评估了泛醇受体抑制剂西地尼布对PDAC细胞的抗肿瘤活性。

方法

使用细胞增殖和结晶紫染色测定法测定西地尼布的抗增殖作用。进行膜联蛋白V / PI染色，放射治疗以及细胞迁移和侵袭试验，以检查西地尼布分别对细胞凋亡，放射敏感性和细胞运动性的影响。应用定量逆转录-PCR（qRT-PCR）和蛋白质印迹分析来阐明西地尼布抗肿瘤活性的分子机制。

结果

我们发现，西地那尼通过抑制抗凋亡蛋白cIAP1，XIAP，MCL-1和survivin降低PDAC细胞增殖和克隆形成存活并诱导凋亡性细胞死亡。与西地那尼的组合可协同提高PDAC细胞对吉西他滨和紫杉醇等化疗药物的敏感性，并增强放射治疗对PDAC细胞生长抑制和凋亡诱导的影响。此外，我们发现西地那尼通过上皮-间充质转化（EMT）标记ZEB1，N-钙黏着蛋白和Snail的表达减少而损害了PDAC细胞的迁移和侵袭。

结论

我们的数据表明，西地尼布可能在PDAC细胞中表现出抗肿瘤活性，并为进一步研究靶向VEGF受体的疗法治疗PDAC的潜力提供了理论依据。