title: Antagonism of sorafenib and regorafenib actions by platelet factors in hepatocellular carcinoma cell lines.
abstract: BACKGROUND
  Platelets are frequently altered in hepatocellular carcinoma (HCC) patients. Platelet lysates (hPL) can enhance HCC cell growth and decrease apoptosis. The aims were to evaluate whether hPL can modulate the actions of sorafenib or regorafenib, two clinical HCC multikinase antagonists.
  
  
  METHODS
  Several human HCC cell lines were grown in the presence and absence of sorafenib or regorafenib, with or without hPL. Growth was measured by MTT assay, apoptosis was assessed by Annexin V and by western blot, and autophagy and MAPK growth signaling were also measured by western blot, and migration and invasion were measured by standard in vitro assays.
  
  
  RESULTS
  Both sorafenib and regorafenib-mediated inhibition of cell growth, migration and invasion were all antagonized by hPL. Drug-mediated apoptosis and decrease in phospho-ERK levels were both blocked by hPL, which also increased anti-apoptotic phospho-STAT, Bax and Bcl-xL levels. Preliminary data, obtained with epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I), included in hPL, revealed that these factors were able to antagonized sorafenib in a proliferation assay, in particular when used in combination.
  
  
  CONCLUSIONS
  Platelet factors can antagonize sorafenib or regorafenib-mediated growth inhibition and apoptosis in HCC cells. The modulation of platelet activity or numbers has the potential to enhance multikinase drug actions.
authors.forename: Rosalba
authors.initials: R
authors.lastname: D'Alessandro
authors.forename: Maria G
authors.initials: MG
authors.lastname: Refolo
authors.forename: Catia
authors.initials: C
authors.lastname: Lippolis
authors.forename: Grazia
authors.initials: G
authors.lastname: Giannuzzi
authors.forename: Nicola
authors.initials: N
authors.lastname: Carella
authors.forename: Caterina
authors.initials: C
authors.lastname: Messa
authors.forename: Aldo
authors.initials: A
authors.lastname: Cavallini
authors.affiliation: Laboratory of Biochemistry, National Institute for Digestive Diseases, IRCCS "Saverio de Bellis", Via Turi 27, 70013, Castellana Grotte, BA, Italy. brianicarr@hotmail.com.
authors.forename: Brian I
authors.initials: BI
authors.lastname: Carr
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001792:Blood Platelets / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000097:blood; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D009361:Neoplasm Invasiveness; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C583557:IGF1 protein, human; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C559147:regorafenib; D009536:Niacinamide; D004815:Epidermal Growth Factor; D007334:Insulin-Like Growth Factor I; D000077157:Sorafenib; D048049:Extracellular Signal-Regulated MAP Kinases