Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Department of Pathology, College of Korean Medicine, Woosuk University, Jeonju-si, Jeollabuk-do, Republic of Korea.
Oxid Med Cell Longev. 2017;2017:5498908. doi: 10.1155/2017/5498908. Epub 2017 Dec 31.
Acquired resistance to cisplatin is the most common reason for the failure of cisplatin chemotherapy. Hederagenin, triterpenoids extracted from ivy leaves, exhibits antitumor activity in various types of cancer. However, the therapeutic potential of hederagenin in head and neck cancer (HNC) has remained unclear. Therefore, we examined the effects of hederagenin in cisplatin-resistant HNC cells and characterized its molecular mechanisms of action in this context. We evaluated the effects of hederagenin treatment on cell viability, apoptosis, reactive oxygen species (ROS) production, glutathione levels, mitochondrial membrane potential (Δm), and protein and mRNA expression in HNC cells. The antitumor effect of hederagenin in mouse tumor xenograft models was also analyzed. Hederagenin selectively induced cell death in both cisplatin-sensitive and cisplatin-resistant HNC cells by promoting changes in Δm and inducing apoptosis. Hederagenin inhibited the Nrf2-antioxidant response element (ARE) pathway and activated p53 in HNC cells, thereby enhancing ROS production and promoting glutathione depletion. These effects were reversed by the antioxidant trolox. Hederagenin activated intrinsic apoptotic pathways via cleaved PARP, cleaved caspase-3, and Bax. The selective inhibitory effects of hederagenin were confirmed in cisplatin-resistant HNC xenograft models. These data suggest that hederagenin induces cell death in resistant HNC cells via the Nrf2-ARE antioxidant pathway.
获得性顺铂耐药是顺铂化疗失败的最常见原因。常春藤叶中提取的三萜类化合物熊果酸具有多种类型癌症的抗肿瘤活性。然而，熊果酸在头颈部癌症（HNC）中的治疗潜力尚不清楚。因此，我们研究了熊果酸在顺铂耐药 HNC 细胞中的作用，并在该背景下对其作用机制进行了表征。我们评估了熊果酸处理对 HNC 细胞活力、细胞凋亡、活性氧（ROS）产生、谷胱甘肽水平、线粒体膜电位（Δm）以及蛋白质和 mRNA 表达的影响。还分析了熊果酸在小鼠肿瘤异种移植模型中的抗肿瘤作用。熊果酸通过改变 Δm 并诱导细胞凋亡，选择性地诱导顺铂敏感和耐药的 HNC 细胞死亡。熊果酸抑制了 HNC 细胞中的 Nrf2-抗氧化反应元件（ARE）通路并激活了 p53，从而增加了 ROS 的产生并促进了谷胱甘肽的耗竭。抗氧化剂 Trolox 可逆转这些作用。熊果酸通过裂解的 PARP、裂解的 caspase-3 和 Bax 激活内在凋亡途径。在顺铂耐药 HNC 异种移植模型中证实了熊果酸的选择性抑制作用。这些数据表明，熊果酸通过 Nrf2-ARE 抗氧化途径诱导耐药 HNC 细胞死亡。
