The over-expression of survivin enhances the chemotherapeutic efficacy of YM155 in human hepatocellular carcinoma
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Hongping Xia1, Jianxiang Chen1, Ming Shi2, Amudha Deivasigamani1, London Lucien P.J. Ooi3,4 and Kam M. Hui1,5,6,7
1 Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore
2 Department of Hepatobiliary Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, P.R. China
3 Department of Surgical Oncology, National Cancer Centre, Singapore
4 Department of General Surgery, Singapore General Hospital, Singapore
5 Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore
6 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
7 Institute of Molecular and Cell Biology, A*STAR, Biopolis Drive Proteos, Singapore
Kam M. Hui, email:
Keywords: Cancer heterogeneity, DNA damage, Hepatocellular carcinoma, Survivin, YM155
Received: October 07, 2014 Accepted: January 04, 2015 Published: January 21, 2015
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.
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