title: Polyphyllin I induced-apoptosis is enhanced by inhibition of autophagy in human hepatocellular carcinoma cells.
abstract: BACKGROUND
  Polyphyllin I (PPI), a bioactive phytochemical isolated from the rhizoma of Paris polyphyllin, exerts preclinical anticancer efficacy in various cancer models. However, the effects of PPI on regulatory human hepatocellular carcinoma (HCC) cell proliferation and its underlying mechanisms remain unknown.
  
  
  OBJECTIVE
  This study investigated the antiproliferation effect of PPI on HCC cells and its underlying mechanisms.
  
  
  METHODS
  Cell viability was measured by MTT assay. Cell death, apoptosis and acidic vesicular organelles (AVOs) formation were determined by flow cytometry. Protein levels were analyzed by Western blot analysis.
  
  
  RESULTS
  PPI induced apoptosis through the caspase-dependent pathway and activated autophagy through the PI3K/AKT/mTOR pathway. Blockade of autophagy by pharmacological inhibitors or RNA interference enhanced the cytotoxicity and antiproliferation effects of PPI. Moreover, chloroquine (CQ) enhanced the antiproliferation effect of PPI on HCC cells via the caspase-dependent apoptosis pathway by inhibiting protective autophagy. Therefore, the combination therapy of CQ and PPI exhibited synergistic effects on HCC cells compared with CQ or PPI alone.
  
  
  CONCLUSIONS
  The current findings strongly indicate that PPI can induce protective autophagy in HCC cells, thereby providing a novel target in potentiating the anticancer effects of PPI and other chemotherapeutic drugs in liver cancer treatment. Moreover, the combination therapy of CQ and PPI is an effective and promising candidate to be further developed as therapeutic agents in the treatment of liver cancer.
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
authors.forename: Ya-Min
authors.initials: YM
authors.lastname: Shi
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
authors.forename: Lei
authors.initials: L
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
authors.forename: Ya-Di
authors.initials: YD
authors.lastname: Geng
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China. Electronic address: cpu_lykong@126.com.
authors.forename: Ling-Yi
authors.initials: LY
authors.lastname: Kong
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology; D004144:Diosgenin / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D015394:Molecular Structure; D012503:Saponins / Q000494:pharmacology; D015398:Signal Transduction
chemical_list: D012503:Saponins; C556217:polyphyllin I; D002738:Chloroquine; D020169:Caspases; D004144:Diosgenin
keywords: Antiproliferation; Apoptosis; Autophagy; Human hepatocellular carcinoma cell; Polyphyllin I