title: The over-expression of survivin enhances the chemotherapeutic efficacy of YM155 in human hepatocellular carcinoma.
abstract: Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. The inability of chemotherapeutic drugs to selectively target HCC tumor cells because of their predominant resistant phenotype to most conventional anticancer agents bestows a major obstacle for the clinical management of HCC. In this report, we have examined and demonstrated the remarkable heterogeneity of expression of survivin and its phosphorylated active form (p-survivin) in HCC patients' tissues and cell lines. Furthermore, the expression of survivin and p-survivin in HCC cell lines was found to be associated with response to the small-molecule survivin suppressant YM155. Therefore, in the HCC cell lines that express elevated level of survivin and p-survivin, YM155 efficiently inhibited their proliferation, induced cell cycle arrest and apoptosis resulting in DNA damage through the dysregulation of cell-cycle checkpoint-related regulatory genes. Importantly, YM155 yielded significantly better therapeutic effect than sorafenib when tested in an orthotopic mouse model using patient-derived HCC xenografts with elevated survivin and p-survivin expression. Our results clearly demonstrated that the level of survivin and p-survivin expression could serve as molecular predictive biomarkers to select potential YM155-responsive patients, in a move towards delivering precision medicine for HCC patients.
authors.affiliation: Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore.
authors.forename: Hongping
authors.initials: H
authors.lastname: Xia
authors.affiliation: Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore.
authors.forename: Jianxiang
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Hepatobiliary Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, P.R. China.
authors.forename: Ming
authors.initials: M
authors.lastname: Shi
authors.affiliation: Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore.
authors.forename: Amudha
authors.initials: A
authors.lastname: Deivasigamani
authors.affiliation: Department of Surgical Oncology, National Cancer Centre, Singapore.|Department of General Surgery, Singapore General Hospital, Singapore.
authors.forename: London Lucien P J
authors.initials: LL
authors.lastname: Ooi
authors.affiliation: Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore.|Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore.|Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|Institute of Molecular and Cell Biology, A*STAR, Biopolis Drive Proteos, Singapore.
authors.forename: Kam M
authors.initials: KM
authors.lastname: Hui
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004249:DNA Damage; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis* / Q000235:genetics; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009285:Naphthoquinones / Q000494:pharmacology*; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics; D000077022:Survivin; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C117749:Birc5 protein, mouse; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D009285:Naphthoquinones; D012097:Repressor Proteins; D000077022:Survivin; C523798:sepantronium
keywords: DNA damage; YM155; cancer heterogeneity; hepatocellular carcinoma; survivin