title: The role of PI3K/mTOR inhibition in combination with sorafenib in hepatocellular carcinoma treatment.
abstract: BACKGROUND
  Deregulated RAS/RAF/MAPK and PI3K/AKT/mTOR signaling pathways are found in hepatocellular carcinoma (HCC). This study aimed to test the inhibitory effects of PI-103 (a small molecule inhibitor of PI3K and mTOR) and sorafenib as single agents and in combination on HCC tumorigenesis in an in vivo xenograft model.
  
  
  METHODS
  In vitro study: Huh7 proliferation was assayed by 3H-thymidine incorporation and by thiazolyl blue tetrazolium bromide (MTT) assay. Western blots were used to detect phosphorylation of the key enzymes in the two pathways. In vivo study: Human HCC cell line Huh7 was inoculated into nude mice s.c. and the mice were treated with sorafenib (20 mg/kg/day) and PI-103 (5 mg/kg, every 4 days). Tumor size was measured every other day. Tumors were isolated for western blot and Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay detection of apoptosis and signaling pathway enzymes.
  
  
  RESULTS
  Our in vitro study found that combination of sorafenib and PI-103 additively inhibited Huh7 proliferation as compared to single-agent treatment. Sorafenib and PI-103 as single agents differentially inhibited or activated key enzymes (MEK, ERK, AKT, mTOR, and S6K) in PI3K/AKT/mTOR and RAS/RAF/MAPK signaling pathways. Combination of sorafenib and PI-103 inhibited all the key enzymes in the two pathways. Our in vivo study demonstrated significant differences between control group, mono-drug groups and drug-combination group (p<0.05). Combination of Sorafenib and PI-103 more efficiently inhibited tumorigenesis as compared to mono-drug treatments (p<0.032).
  
  
  CONCLUSIONS
  The combination of PI-103 and sorafenib has the advantage over mono-drug therapy on inhibition of HCC cell proliferation and tumorigenesis by inhibiting both PI3K/AKT/mTOR and RAS/RAF/MAPK signaling pathways.
authors: Department of Surgery, University of Kentucky, College of Medicine, Lexington, KY, USA. rgeda2@uky.edu
authors: Roberto
authors: R
authors: Gedaly
authors: Paul
authors: P
authors: Angulo
authors: Changguo
authors: C
authors: Chen
authors: Kate Townsend
authors: KT
authors: Creasy
authors: Brett T
authors: BT
authors: Spear
authors: Jonathan
authors: J
authors: Hundley
authors: Michael F
authors: MF
authors: Daily
authors: Malay
authors: M
authors: Shah
authors: B Mark
authors: BM
authors: Evers
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001557:Benzenesulfonates / Q000008:administration & dosage; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D005663:Furans / Q000008:administration & dosage; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009536:Niacinamide / Q000031:analogs & derivatives; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D010671:Phenylurea Compounds; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D001557:Benzenesulfonates; D005663:Furans; D009536:Niacinamide; D051058:Oncogene Protein v-akt; D010671:Phenylurea Compounds; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D000077157:Sorafenib; D058570:TOR Serine-Threonine Kinases; C522973:PI103; C546842:MTOR protein, human