title: Smac mimetic SM-164 potentiates APO2L/TRAIL- and doxorubicin-mediated anticancer activity in human hepatocellular carcinoma cells.
abstract: BACKGROUND
  The members of inhibitor of apoptosis proteins (IAPs) family are key negative regulators of apoptosis. Overexpression of IAPs are found in hepatocellular carcinoma (HCC), and can contribute to chemotherapy resistance and recurrence of HCC. Small-molecule Second mitochondria-derived activator of caspases (Smac) mimetics have recently emerged as novel anticancer drugs through targeting IAPs. The specific aims of this study were to 1) examine the anticancer activity of Smac mimetics as a single agent and in combination with chemotherapy in HCC cells, and 2) investigate the mechanism of anticancer action of Smac mimetics.
  
  
  METHODS
  Four HCC cell lines, including SMMC-7721, BEL-7402, HepG2 and Hep3B, and 12 primary HCC cells were used in this study. Smac mimetic SM-164 was used to treat HCC cells. Cell viability, cell death induction and clonal formation assays were used to evaluate the anticancer activity. Western blotting analysis and a pancaspase inhibitor were used to investigate the mechanisms.
  
  
  RESULTS
  Although SM-164 induced complete cIAP-1 degradation, it displayed weak inhibitory effects on the viability of HCC cells. Nevertheless, SM-164 considerably potentiated Apo2 ligand or TNF-related apoptosis-inducing ligand (APO2L/TRAIL)- and Doxorubicin-mediated anticancer activity in HCC cells. Mechanistic studies demonstrated that SM-164 in combination with chemotherapeutic agents resulted in enhanced activation of caspases-9, -3 and cleavage of poly ADP-ribose polymerase (PARP), and also led to decreased AKT activation.
  
  
  CONCLUSIONS
  Smac mimetics can enhance chemotherapeutic-mediated anticancer activity by enhancing apoptosis signaling and suppressing survival signaling in HCC cells. This study suggests Smac mimetics are potential therapeutic agents for HCC.
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China. zhangshuijun@zzu.edu.cn
authors.forename: Shuijun
authors.initials: S
authors.lastname: Zhang
authors.forename: Gongquan
authors.initials: G
authors.lastname: Li
authors.forename: Yongfu
authors.initials: Y
authors.lastname: Zhao
authors.forename: Guangzhi
authors.initials: G
authors.lastname: Liu
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Xiuxian
authors.initials: X
authors.lastname: Ma
authors.forename: Dexu
authors.initials: D
authors.lastname: Li
authors.forename: Yang
authors.initials: Y
authors.lastname: Wu
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Lu
mesh_terms: D000071478:APOBEC Deaminases; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D032701:Biomimetics; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003564:Cytidine Deaminase / Q000378:metabolism; D004317:Doxorubicin / Q000008:administration & dosage; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000008:administration & dosage / Q000138:chemical synthesis; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000008:administration & dosage / Q000138:chemical synthesis; D009124:Muscle Proteins / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D014230:Triazoles / Q000008:administration & dosage*
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D019086:Bridged Bicyclo Compounds, Heterocyclic; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D009124:Muscle Proteins; C533467:SM 164; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014230:Triazoles; D004317:Doxorubicin; D000071478:APOBEC Deaminases; C120388:APOBEC2 protein, human; D003564:Cytidine Deaminase