title: Ulinastatin reduces the resistance of liver cancer cells to epirubicin by inhibiting autophagy.
abstract: During chemotherapy, drug resistance caused by autophagy remains a major challenge to successful treatment of cancer patients. The purpose of this study is to show that ulinastatin (UTI), a trypsin inhibitor, could reduce the resistance of liver cancer cells to chemotherapeutic agent epirubicin (EPI). We achieved this conclusion by analyzing the effect of EPI alone or UTI plus EPI on SMMC-7721 and MHCC-LM3 liver cancer cells. We also generated an EPI-resistant liver cancer cell line (MHCC-LM3er cells), and found that UTI could sensitize the LM3er cells to EPI. Autophagy usually functions to protect cancer cells during chemotherapy. Our study showed that UTI inhibited the autophagy induced by EPI in liver cancer cells, which promoted apoptosis, and therefore, reduced the resistance of the cancer cells to EPI. Further studies showed that the UTI-mediated inhibition on autophagy was achieved by inhibiting transcriptional factor nuclear factor-κB (NF-κB) signaling pathway. To verify our results in vivo, we injected MHCC-LM3 liver cancer cells or EPI-resistant LM3er cells into mice, and found that EPI could only effectively inhibit the growth of tumor in MHCC-LM3 cell-injected mice, but not in LM3er cell-injected mice. However, when UTI was also administered, the growth of tumor was inhibited in the MHCC-LM3er cell-injected mice as well. Our results suggest that UTI may be used in combination with anti-cancer drugs, such as EPI, to improve the outcome of cancer therapy.
authors: Department of General Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200438, China.
authors: Bin
authors: B
authors: Song
authors: Department of Nephrology, Changhai Hospital, Second Military Medical University, Shanghai, 200438, China.
authors: Qi
authors: Q
authors: Bian
authors: Department of General Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200438, China.
authors: Cheng Hao
authors: CH
authors: Shao
authors: Department of General Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200438, China.
authors: Gang
authors: G
authors: Li
authors: Department of General Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200438, China.
authors: An An
authors: AA
authors: Liu
authors: Department of General Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200438, China.
authors: Wei
authors: W
authors: Jing
authors: Department of General Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200438, China.
authors: Rui
authors: R
authors: Liu
authors: Department of General Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200438, China.
authors: Yi-Jie
authors: YJ
authors: Zhang
authors: Department of General Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200438, China.
authors: Ying-Qi
authors: YQ
authors: Zhou
authors: Department of General Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200438, China.
authors: Xian-Gui
authors: XG
authors: Hu
authors: Department of General Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200438, China.
authors: Gang
authors: G
authors: Jin
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D015251:Epirubicin / Q000494:pharmacology*; D006023:Glycoproteins / Q000494:pharmacology*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014361:Trypsin Inhibitors / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D014408:Biomarkers, Tumor; D006023:Glycoproteins; D012333:RNA, Messenger; D014361:Trypsin Inhibitors; D015251:Epirubicin; C028665:urinastatin