title: Effects of low concentrations of regorafenib and sorafenib on human HCC cell AFP, migration, invasion, and growth in vitro.
abstract: Sorafenib was shown in clinical trial to enhance survival in hepatocellular carcinoma (HCC) patients, but with minimal tumor shrinkage. To correlate several indices of HCC growth at various drug concentrations, HCC cells were grown in various low concentrations of two multikinase inhibitors, regorafenib (Stivarga) and sorafenib (Nexavar) and their effects were examined on alpha-fetoprotein (AFP), cell growth, migration, and invasion. In two AFP positive human HCC cell lines, AFP was inhibited at 0.1-1 µM drug concentrations. Cell migration and invasion were also inhibited at similar low drug concentrations. However, 10-fold higher drug concentrations were required to inhibit cell growth in both AFP positive and negative cells. To investigate this concentration discrepancy of effects, cells were then grown for prolonged times and sub-cultured in low drug concentrations and then their growth was re-tested. The growth in these drug-exposed cells was found to be slower than cells without prior drug exposure and they were also more sensitive to subsequent drug challenge. Evidence was also found for changes in cell signaling pathways in these slow-growth cells. Low multikinase inhibitor concentrations thus modulate several aspects of HCC cell biology.
authors.affiliation: Laboratory of Biochemistry, National Institute for Digestive Diseases, IRCCS S. de Bellis, Castellana Grotte (BA), Italy. brianicarr@hotmail.com
authors.forename: Brian I
authors.initials: BI
authors.lastname: Carr
authors.forename: Rosalba
authors.initials: R
authors.lastname: D'Alessandro
authors.forename: Maria G
authors.initials: MG
authors.lastname: Refolo
authors.forename: Palma A
authors.initials: PA
authors.lastname: Iacovazzi
authors.forename: Catia
authors.initials: C
authors.lastname: Lippolis
authors.forename: Caterina
authors.initials: C
authors.lastname: Messa
authors.forename: Aldo
authors.initials: A
authors.lastname: Cavallini
authors.forename: Mario
authors.initials: M
authors.lastname: Correale
authors.forename: Antonio
authors.initials: A
authors.lastname: Di Carlo
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D009361:Neoplasm Invasiveness; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D013997:Time Factors; D000509:alpha-Fetoproteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C097353:AFP protein, human; D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D000509:alpha-Fetoproteins; C559147:regorafenib; D009536:Niacinamide; D000077157:Sorafenib