Salubrinal Enhances Doxorubicin Sensitivity in Human Cholangiocarcinoma Cells Through Promoting DNA Damage.

Abstract

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.

• Authors: Wenjing Yu, Yuancai Xiang, Guosong Luo, Xiaofang Zhao, Bin Xiao, Ying Cheng, Chunhong Feng, Chunyan Duan, Xianming Xia, Vincent Kam Wai Wong, Rongyang Dai
• Journal: Cancer biotherapy & radiopharmaceuticals (Cancer Biother Radiopharm) Vol. 33 Issue 6 Pg. 258-265 (Aug 2018) ISSN: 1557-8852 [Electronic] United States
• PMID: 29957018 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Cinnamates
• Eukaryotic Initiation Factor-2
• Reactive Oxygen Species
• salubrinal
• Doxorubicin
• Thiourea

Topics

• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Bile Duct Neoplasms (drug therapy, genetics, pathology)
• Bile Ducts, Intrahepatic (pathology)
• Cell Line, Tumor
• Cholangiocarcinoma (drug therapy, genetics, pathology)
• Cinnamates (pharmacology, therapeutic use)
• DNA Damage (drug effects)
• Doxorubicin (pharmacology, therapeutic use)
• Drug Resistance, Neoplasm (drug effects, genetics)
• Drug Synergism
• Eukaryotic Initiation Factor-2 (antagonists & inhibitors)
• Humans
• Reactive Oxygen Species (metabolism)
• Thiourea (analogs & derivatives, pharmacology, therapeutic use)