title: Imperatorin acts as a cisplatin sensitizer via downregulating Mcl-1 expression in HCC chemotherapy.
abstract: Acquisition of cisplatin resistance is the common and critical limitation for hepatocellular carcinoma (HCC) therapy. Our study was aimed to determine whether there were conditions under which the addition of imperatorin would reverse the resistance of HCC cells to cisplatin-based therapy. In this study, we found that addition of imperatorin significantly enhanced the cytotoxicity of cisplatin to HCC cells. Since the Mcl-1 was overexpressed in HCC cell lines (HepG2, HepG3B, PLC, Huh7) compared with normal liver cell line (L-O2), we found that the Mcl-1 expression was downregulated by imperatorin but not influenced by cisplatin in HCC cells. In addition, our results showed the combination of imperatorin and cisplatin induced apoptosis and ∆Ψm collapse more significantly compared with treatment of imperatorin or cisplatin alone. Furthermore, the imperatorin-induced sensitization for cisplatin-cytotoxicity to HCC cells was abolished by the transfection of Mcl-1 expression plasmid. Finally, we found that the addition of imperatorin significantly reversed the resistance to cisplatin in cisplatin-resistant HCC cells, which was Mcl-1 dependent. In summary, our study revealed that combination with imperatorin could enhance the antitumor activity of cisplatin via targeting Mcl-1 and reverse the resistance to cisplatin in HCC.
authors.affiliation: Department of Anesthesiology, Critical Care and Pain Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, West College Road No.109, Wenzhou, Zhejiang Province, China 325027.
authors.forename: Jianjian
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Gastroenterology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, West College Road No.109, Wenzhou City, Zhejiang Province, China, 325027.
authors.forename: Changlong
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Anesthesiology, Critical Care and Pain Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, West College Road No.109, Wenzhou, Zhejiang Province, China 325027.
authors.forename: Bihuan
authors.initials: B
authors.lastname: Cheng
authors.affiliation: Department of Infectious Disease, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, West College Road No.109, Wenzhou City, Zhejiang Province, China, 325027.
authors.forename: Lingxiang
authors.initials: L
authors.lastname: Jin
authors.affiliation: Department of Infectious Disease, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, West College Road No.109, Wenzhou City, Zhejiang Province, China, 325027.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, Critical Care and Pain Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, West College Road No.109, Wenzhou, Zhejiang Province, China 325027.
authors.forename: Yuqiang
authors.initials: Y
authors.lastname: Gong
authors.affiliation: Department of Infectious Disease, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, West College Road No.109, Wenzhou City, Zhejiang Province, China, 325027.
authors.forename: Wei
authors.initials: W
authors.lastname: Lin
authors.affiliation: Department of Infectious Disease, The First Affiliated Hospital of Wenzhou Medical University, FuXue lane No.2, Wenzhou, Zhejiang Province, China 325000. wzzhenzhenpan@126.com.
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Pan
authors.affiliation: Department of Infectious Disease, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, West College Road No.109, Wenzhou City, Zhejiang Province, China, 325027. wenzhouchenweipan@126.com.
authors.forename: Chenwei
authors.initials: C
authors.lastname: Pan
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor / Q000187:drug effects; D002470:Cell Survival; D002945:Cisplatin / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D011564:Furocoumarins / Q000737:chemistry*; D056945:Hep G2 Cells / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D016133:Polymerase Chain Reaction
chemical_list: D011564:Furocoumarins; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C031534:imperatorin; D002945:Cisplatin
keywords: Apoptosis; Cisplatin; HCC; Imperatorin; Mcl-1