title: Reversibility of regorafenib effects in hepatocellular carcinoma cells.
abstract: OBJECTIVE
  Multikinase growth inhibitors inhibit their target kinases with varying potency. Patients often require lower doses or therapy breaks due to drug toxicities. To evaluate the effects of drug withdrawal on hepatocellular carcinoma cells after incubation with growth-inhibitory concentrations of regorafenib, cell growth, migration and invasion, and signaling were examined.
  
  
  METHODS
  Cell proliferation, motility, and invasion were analyzed by MTT, wound healing, and invasion assays, respectively, and MAPK pathway protein markers were analyzed by Western blot.
  
  
  RESULTS
  After regorafenib removal, cell growth, migration, and invasion recovered. Repeated drug exposure resulted in changes in cell growth patterns. Recovery could be blocked by sub-growth-inhibitory concentrations of either doxorubicin or vitamin K1. Recovery of growth was associated with increased phospho-JNK, phospho-p38, and phospho-STAT3 levels. The recovery of growth, migration, and signaling were blocked by a JNK inhibitor.
  
  
  CONCLUSIONS
  Removal of regorafenib from growth-inhibited cells resulted in a JNK-dependent recovery of growth and migration.
authors: Rosalba
authors: R
authors: D'Alessandro
authors: Maria G
authors: MG
authors: Refolo
authors: Catia
authors: C
authors: Lippolis
authors: Caterina
authors: C
authors: Messa
authors: Aldo
authors: A
authors: Cavallini
authors: Roberta
authors: R
authors: Rossi
authors: Leonardo
authors: L
authors: Resta
authors: Antonio
authors: A
authors: Di Carlo
authors: Brian I
authors: BI
authors: Carr
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009361:Neoplasm Invasiveness; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D010837:Vitamin K 1 / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D011725:Pyridines; C559147:regorafenib; D004317:Doxorubicin; D010837:Vitamin K 1
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