title: Therapeutic effects of artesunate in hepatocellular carcinoma: repurposing an ancient antimalarial agent.
abstract: OBJECTIVE
  Artemisinins are antimalarial drugs that exert potent anticancer activity. We evaluated the effects of artesunate, a semisynthetic derivative of artemisinin, on tumor growth, angiogenesis, the unfolded protein response, and chemoresistance in hepatocellular carcinoma.
  
  
  METHODS
  The effect of artesunate was examined in HepG2 and BWTG3 cells under normoxic and hypoxic conditions and in a diethylnitrosamine-induced mouse model. Histology was performed with hematoxylin/eosin and reticulin staining. The expression of chemoresistance-related transporters and angiogenic and unfolded protein response factors was determined. Cytotoxicity was assessed by alanine and aspartate transaminase, lactate dehydrogenase, water-soluble tetrazolium salt, and caspase-3 activity assays. Small animal imaging was performed using dynamic contrast-enhanced MRI and choline PET to assess tumor progression.
  
  
  RESULTS
  Artesunate dose dependently reduced cell viability (from 50 μmol/l; P<0.05) and increased caspase-3 activity (P<0.05) in HepG2 and BWTG3 cells. These effects were enhanced by hypoxia (from 12.5 μmol/l; P<0.01). Moreover, artesunate downregulated vascular endothelial growth factor and placental growth factor expression in vitro (both P<0.05) and in vivo (both P<0.01). In mice, artesunate decreased vessel density and tumor burden (both P<0.05). These in-vivo effects were enhanced by combination with sorafenib (P<0.05 and P=0.07, respectively), without apparent hepatotoxicity. Furthermore, artesunate modulated the unfolded protein response in vitro and in vivo, increasing proapoptotic signaling, and did not induce doxorubicin chemoresistance.
  
  
  CONCLUSIONS
  These findings indicate that artesunate could offer a new approach to the therapy of hepatocellular carcinoma. Clinical trials with artesunate as monotherapy or in combination with current hypoxia-inducing approaches are necessary.
authors.affiliation: aDepartment of Hepatology and Gastroenterology bInfinity Imaging Lab, Medisip, iMinds cDepartment of Respiratory Medicine dGROUP-ID Consortium, Ghent University eDepartment of Pathology, Ghent University Hospital fUnit Immunoregulation and Mucosal Immunology, VIB Inflammation Research Center, Ghent, Belgium.
authors.forename: Yves-Paul
authors.initials: YP
authors.lastname: Vandewynckel
authors.forename: Debby
authors.initials: D
authors.lastname: Laukens
authors.forename: Anja
authors.initials: A
authors.lastname: Geerts
authors.forename: Chris
authors.initials: C
authors.lastname: Vanhove
authors.forename: Benedicte
authors.initials: B
authors.lastname: Descamps
authors.forename: Isabelle
authors.initials: I
authors.lastname: Colle
authors.forename: Lindsey
authors.initials: L
authors.lastname: Devisscher
authors.forename: Eliene
authors.initials: E
authors.lastname: Bogaerts
authors.forename: Annelies
authors.initials: A
authors.lastname: Paridaens
authors.forename: Xavier
authors.initials: X
authors.lastname: Verhelst
authors.forename: Christophe
authors.initials: C
authors.lastname: Van Steenkiste
authors.forename: Louis
authors.initials: L
authors.lastname: Libbrecht
authors.forename: Bart N
authors.initials: BN
authors.lastname: Lambrecht
authors.forename: Sophie
authors.initials: S
authors.lastname: Janssens
authors.forename: Hans
authors.initials: H
authors.lastname: Van Vlierberghe
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D037621:Artemisinins / Q000008:administration & dosage / Q000627:therapeutic use*; D000077332:Artesunate; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D058492:Drug Repositioning / Q000379:methods*; D019008:Drug Resistance, Neoplasm; D004359:Drug Therapy, Combination; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D010671:Phenylurea Compounds / Q000008:administration & dosage; D000077157:Sorafenib; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D037621:Artemisinins; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077332:Artesunate; D000077157:Sorafenib