1] Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania Perelman School of Medicine, 415 Curie Boulevard, Clinical Research Building, Philadelphia, PA, USA [2] Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania Perelman School of Medicine, 415 Curie Boulevard, Clinical Research Building, Philadelphia, PA, USA.
Br J Cancer. 2014 Apr 15;110(8):2116-22. doi: 10.1038/bjc.2014.98. Epub 2014 Feb 25.
In this study, we evaluate whether the use of biliverdin (BV), a natural non-toxic antioxidant product of haeme catabolism, can suppress head and neck squamous cell carcinoma (HNSCC) cell proliferation and improve the tumour survival both in vitro and in vivo. Furthermore, we investigate whether this therapeutic outcome relies on BV's potent antioxidant effect on reactive oxygen species (ROS)-mediated signalling.
Two well-characterised HNSCC cell lines and a mouse model with human HNSCC were used for this study. In vitro, the effect of BV on ROS was assayed. Subsequently, critical regulatory proteins involved in growth, antiapoptotic, and angiogenic pathways were investigated by western blot analysis. In addition, the antiproliferative effect of BV was also evaluated using the clonogenic assay. Moreover, tumour growth inhibition was assessed using a mouse model with HNSCC.
Biliverdin treatment resulted in decreased ROS, leading to suppression of proliferation and angiogenesis pathways of HNSCC, significantly decreasing the expression and phosphorylation of oncogenic factors such as epidermal growth factor receptor (EGFR), phosphorylation of Akt, and expression of angiogenic marker and transcription factor, hypoxia-inducible factor1-α (HIF1-α). Furthermore, this downregulation of ROS by BV led to a significant suppression of tumour growth in vivo.
Our study demonstrates the efficacy of a novel therapeutic approach using BV as an antitumour agent against HNSCC through its effect on EGFR/Akt and HIF1-α/angiogenesis signal transduction pathways. Our findings indicate that BV's inhibitory effect on these tumorigenic pathways relies on its antioxidant effect, and may extend its therapeutic potential to other solid cancers.
在这项研究中，我们评估了胆红素（BV）的使用是否可以抑制头颈部鳞状细胞癌（HNSCC）细胞的增殖，并提高体外和体内的肿瘤存活率。此外，我们还研究了这种治疗效果是否依赖于 BV 对活性氧（ROS）介导的信号的强大抗氧化作用。
本研究使用了两种经过良好特征描述的 HNSCC 细胞系和一种带有人类 HNSCC 的小鼠模型。在体外，检测了 BV 对 ROS 的影响。随后，通过 Western blot 分析研究了参与生长、抗凋亡和血管生成途径的关键调节蛋白。此外，还使用集落形成测定法评估了 BV 的抗增殖作用。此外，还使用带有 HNSCC 的小鼠模型评估了肿瘤生长抑制作用。
BV 处理导致 ROS 减少，从而抑制了 HNSCC 的增殖和血管生成途径，显著降低了致癌因子如表皮生长因子受体（EGFR）的表达和磷酸化、Akt 的磷酸化以及血管生成标记物和转录因子缺氧诱导因子 1-α（HIF1-α）的表达。此外，BV 对 ROS 的这种下调导致体内肿瘤生长显著抑制。
我们的研究表明，BV 作为一种针对 HNSCC 的抗肿瘤药物，通过其对 EGFR/Akt 和 HIF1-α/血管生成信号转导途径的作用，具有有效的治疗方法。我们的研究结果表明，BV 对这些肿瘤发生途径的抑制作用依赖于其抗氧化作用，并且可能将其治疗潜力扩展到其他实体瘤。
