1 State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology , Taipei, China .
2 Department of Biochemistry and Molecular Biology, Southwest Medical University , Luzhou, China .
Cancer Biother Radiopharm. 2018 Aug;33(6):258-265. doi: 10.1089/cbr.2018.2447. Epub 2018 Jun 29.
Cholangiocarcinoma (CCA) is a highly malignant and aggressive tumor of the bile duct that arises from epithelial cells. Chemotherapy is an important treatment strategy for CCA patients, but its efficacy remains limited due to drug resistance. Salubrinal, an inhibitor of eukaryotic translation initiation factor 2 alpha (eIF2α), has been reported to affect antitumor activities in cancer chemotherapy. In this study, the authors investigated the effect of salubrinal on the chemosensitivity of doxorubicin in CCA cells. They showed that doxorubicin induces CCA cell death in a dose- and time-dependent manner. Doxorubicin triggers reactive oxygen species (ROS) generation and induces DNA damage in CCA cells. In addition, ROS inhibitor N-acetylcysteine (NAC) pretreatment inhibits doxorubicin-induced CCA cell death. Importantly, these data demonstrate a synergistic death induction effect contributed by the combination of salubrinal and doxorubicin in CCA cells. It is notable that salubrinal promotes doxorubicin-induced ROS production and DNA damage in CCA cells. Taken together, these data suggest that salubrinal enhances the sensitivity of doxorubicin in CCA cells through promoting ROS-mediated DNA damage.
胆管癌（CCA）是一种起源于上皮细胞的高度恶性和侵袭性胆管肿瘤。化疗是 CCA 患者的重要治疗策略，但由于耐药性，其疗效仍然有限。Salubrinal 是一种真核翻译起始因子 2α（eIF2α）的抑制剂，据报道它会影响癌症化疗中的抗肿瘤活性。在这项研究中，作者研究了 salubrinal 对 CCA 细胞中多柔比星化疗敏感性的影响。结果表明，多柔比星以剂量和时间依赖的方式诱导 CCA 细胞死亡。多柔比星在 CCA 细胞中触发活性氧（ROS）的产生并诱导 DNA 损伤。此外，ROS 抑制剂 N-乙酰半胱氨酸（NAC）预处理可抑制多柔比星诱导的 CCA 细胞死亡。重要的是，这些数据表明，在 CCA 细胞中，salubrinal 和多柔比星的联合使用具有协同的死亡诱导作用。值得注意的是，salubrinal 促进 CCA 细胞中多柔比星诱导的 ROS 产生和 DNA 损伤。总之，这些数据表明，salubrinal 通过促进 ROS 介导的 DNA 损伤增强了多柔比星在 CCA 细胞中的敏感性。
