title: Enhanced autophagic activity of artocarpin in human hepatocellular carcinoma cells through improving its solubility by a nanoparticle system.
abstract: BACKGROUND
  Hepatocellular carcinoma (HCC) is the most common liver cancer worldwide, with poor prognosis and resistance to chemotherapy. This gives novel cancer treatment methods an overwhelming significance. Natural products offer great resources of developing new and effective chemopreventive or chemotherapeutic agents. Artocarpus communis extracts and its active constituent, prenylated flavonoid artocarpin induce human hepatocellular carcinoma cell death. However, the poor water solubility drawbacks of artocarpin restrict its clinical application and bioavailability.
  
  
  OBJECTIVE
  This study developed the artocarpin nanoparticle system to overcome the poor water solubility drawbacks and investigated the improvement of therapeutic efficacy of artocarpin by adopting novel nanoparticle delivery strategy.
  
  
  METHODS
  Antiproliferative activity of artocarpin was evaluated by MTT assay. Cell morphology observation by microscope, DNA fragmentation assay, cell cycle analysis, Annexin V apoptosis cell staining, monodansylcadaverine and acridine orange staining and immunoblot analysis were used to evaluate the induction of autophagy by artocarpin. The determination of particle size, amorphous transformation, hydrogen-bond formation, yield, encapsulation efficiency and the solubility study were used to investigate the solubility enhancement mechanism of artocarpin.
  
  
  RESULTS
  The present study demonstrates that the anticancer effect of artocarpin in HepG2 and PLC/PRF/5 hepatoma cells is mediated through the autophagic cell death mechanism. Results also demonstrated that artocarpin nanoparticles enhanced the solubility of artocarpin by reducing particle size, transforming high energy amorphous state, and forming hydrogen bond with excipients. Additionally, ArtN exhibited better autophagic cytotoxicity compared to free artocarpin.
  
  
  CONCLUSIONS
  This work reveals the antihepatoma activity of artocarpin by inducing autophagic cell death and the improvement of therapeutic efficacy of artocarpin by adopting novel nanoparticle delivery strategy. The research provided a basis of ArtN could be explored as a low-dose alternative of artocarpin in anticancer treatment and research applications.
authors.affiliation: Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC.
authors.forename: Cheng-Wei
authors.initials: CW
authors.lastname: Tzeng
authors.affiliation: Department of Medical Imaging, Chi Mei Medical Center, Tainan, Taiwan, ROC; Department of Medical Imaging and Radiological Science, College of Health Sciences, Central Taiwan University of Science and Technology, Taichung City, Taiwan, ROC.
authors.forename: Wen-Sheng
authors.initials: WS
authors.lastname: Tzeng
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC; Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC.
authors.forename: Liang-Tzung
authors.initials: LT
authors.lastname: Lin
authors.affiliation: Department of Nursing, Division of Basic Medical Sciences, and Chronic Diseases and Health Promotion Research Center, Chang Gung Institute of Technology, Chia-Yi, Taiwan, ROC; Research Center for Industry of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan, ROC.
authors.forename: Chiang-Wen
authors.initials: CW
authors.lastname: Lee
authors.affiliation: Department of Fragrance and Cosmetic Science, College of Pharmacy, Kaohsiung Medical University, 100, Shih-Chuan 1st Road, Kaohsiung 807, Taiwan, ROC.; Institute of Biomedical Sciences, Sun Yat-Sen University, Kaohsiung, Taiwan, ROC.. Electronic address: flyen@kmu.edu.tw.
authors.forename: Feng-Lin
authors.initials: FL
authors.lastname: Yen
authors.affiliation: Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC; School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, 100, Shih-Chuan 1st Road, Kaohsiung 807, Taiwan, ROC.. Electronic address: aalin@kmu.edu.tw.
authors.forename: Chun-Ching
authors.initials: CC
authors.lastname: Lin
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D031622:Artocarpus / Q000737:chemistry; D001343:Autophagy / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D053938:DNA Fragmentation; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D037241:Mannose-Binding Lectins / Q000494:pharmacology*; D053758:Nanoparticles / Q000737:chemistry; D010316:Particle Size; D037121:Plant Lectins / Q000494:pharmacology*; D012995:Solubility
chemical_list: D000970:Antineoplastic Agents; D037241:Mannose-Binding Lectins; D037121:Plant Lectins; C090683:artocarpin lectin
keywords: Artocarpin; Autophagy; Hepatocellular carcinoma; Nanoparticle; Solubility