Department of Oral Biology, Dental College of Georgia, Augusta University, Augusta, GA, USA.
Department of Pediatrics, Emory Children's Center, Emory University, Atlanta, GA, USA.
J Hematol Oncol. 2018 Jun 20;11(1):85. doi: 10.1186/s13045-018-0623-3.
Inhibition of metastasis of head and neck squamous cell carcinoma (HNSCC) is one of the most important challenges in cancer treatment. Src, a non-receptor tyrosine kinase, has been implicated as a key promoter in tumor progression and metastasis of HNSCC. However, Src therapy for HNSCC is limited by lack of efficient in vivo delivery and underlying mechanisms remain elusive.
Src knockdown cells were achieved by lentiviral-mediated interference. Cell migration and invasion were examined by wound healing and Transwell assays. Protein levels were determined by Western blot and/or immunohistochemistry. The Src inhibitor saracatinib was loaded into self-assembling nanoparticles by the solvent evaporation method. An experimental metastasis mouse model was generated to investigate the drug efficacy in metastasis.
Blockade of Src kinase activity by saracatinib effectively suppressed invasion and metastasis of HNSCC. Mechanistic assessment of the drug effects in HNSCC cells showed that saracatinib induced suppression of Src-dependent invasion/metastasis through downregulating the expression levels of Vimentin and Snail proteins. In tests in mice, saracatinib loaded into the novel multifunctional nanoparticles exhibited superior effects on suppression of HNSCC metastasis compared with the free drug, which is mainly attributed to highly specific and efficient tumor-targeted drug delivery system.
These findings and advances are of great importance to the development of Src-targeted nanomedicine as a more effective therapy for metastatic HNSCC.
抑制头颈部鳞状细胞癌（HNSCC）的转移是癌症治疗中最重要的挑战之一。Src 是一种非受体酪氨酸激酶，它被认为是促进 HNSCC 肿瘤进展和转移的关键因素。然而，Src 治疗 HNSCC 受到体内递送效率低下的限制，其潜在机制仍不清楚。
通过慢病毒介导的干扰实现 Src 敲低细胞。通过划痕愈合和 Transwell 分析检测细胞迁移和侵袭。通过 Western blot 和/或免疫组化测定蛋白水平。采用溶剂蒸发法将 Src 抑制剂 Saracatinib 载入自组装纳米颗粒。构建实验性转移小鼠模型以研究药物在转移中的疗效。
Saracatinib 抑制 Src 激酶活性可有效抑制 HNSCC 的侵袭和转移。对 HNSCC 细胞中药物作用的机制评估表明，Saracatinib 通过下调波形蛋白和 Snail 蛋白的表达水平，诱导 Src 依赖性侵袭/转移的抑制。在小鼠试验中，载有 Saracatinib 的新型多功能纳米颗粒在抑制 HNSCC 转移方面表现出优于游离药物的效果，这主要归因于高度特异和有效的肿瘤靶向药物递送系统。
这些发现和进展对开发 Src 靶向纳米医学作为治疗转移性 HNSCC 的更有效疗法具有重要意义。
