title: Activity of the mTOR inhibitor RAD001, the dual mTOR and PI3-kinase inhibitor BEZ235 and the PI3-kinase inhibitor BKM120 in hepatocellular carcinoma.
abstract: BACKGROUND
  Hepatocellular carcinoma (HCC) is one of the most deadly cancers worldwide with only few therapeutic options for patients with advanced disease. There is growing evidence indicating that activation of the PI3K/Akt/mTOR pathway plays an important role in HCC and therefore represents a promising target for novel therapeutic approaches. The aim of this study was to evaluate and compare the antitumour activity of the mTOR inhibitor RAD001, the dual mTOR and PI3-kinase inhibitor BEZ235 and the PI3-kinase inhibitor BKM120 in vitro and in vivo.
  
  
  METHODS
  The antitumour effects of RAD001, BEZ235 and BKM120 were analysed in seven hepatoma cell lines as mono and combination therapy with Doxorubicin, Cisplatin, Irinotecan or 5-Flourouracil in vitro and in xenografts. Cell-cycle progression, apoptosis, and autophagy were analysed. Furthermore, effects on mitochondrial respiration and glycolysis were assessed.
  
  
  RESULTS
  Treatment with RAD001, BEZ235 and BKM120 markedly reduced tumour cell viability. Combination of PI3K inhibitors with chemotherapy was most effective. RAD001, BEZ235 and BKM120 reduced tumour growth mainly by inhibiting cell-cycle progression rather than by inducing apoptosis. Interestingly, the antitumour effects were strongly associated with a reduction of mitochondrial respiration. BKM120, which exhibited the strongest antiproliferative effect, most strongly impaired oxidative phosphorylation compared with the other drugs.
  
  
  CONCLUSIONS
  In this study, BKM120 showed the strongest antitumour activity. Our findings suggest impairment of mitochondrial function as a relevant mechanism of BKM120. Moreover, combination of PI3K and mTOR inhibitors with cytotoxic agents could be promising option for non-cirrhotic HCC patients.
authors.affiliation: Department of Hepatology, Gastroenterology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Martha M
authors.initials: MM
authors.lastname: Kirstein
authors.forename: Aristeidis E
authors.initials: AE
authors.lastname: Boukouris
authors.forename: Deepika
authors.initials: D
authors.lastname: Pothiraju
authors.forename: Laura E
authors.initials: LE
authors.lastname: Buitrago-Molina
authors.forename: Silke
authors.initials: S
authors.lastname: Marhenke
authors.forename: Jutta
authors.initials: J
authors.lastname: Schütt
authors.forename: Johanna
authors.initials: J
authors.lastname: Orlik
authors.forename: Florian
authors.initials: F
authors.lastname: Kühnel
authors.forename: Jan
authors.initials: J
authors.lastname: Hegermann
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.forename: Arndt
authors.initials: A
authors.lastname: Vogel
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000704:Analysis of Variance; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D019069:Cell Respiration / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology; D000068338:Everolimus; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D015151:Immunoblotting; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D000077146:Irinotecan; D008113:Liver Neoplasms / Q000188:drug therapy*; D009025:Morpholines / Q000494:pharmacology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines / Q000494:pharmacology*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000631:Aminopyridines; D007093:Imidazoles; D009025:Morpholines; C571178:NVP-BKM120; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines; D000077146:Irinotecan; D004317:Doxorubicin; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D002945:Cisplatin; C531198:dactolisib; D020123:Sirolimus; D002166:Camptothecin