title: Comparative Metabolomic Profiling of Hepatocellular Carcinoma Cells Treated with Sorafenib Monotherapy vs. Sorafenib-Everolimus Combination Therapy.
abstract: BACKGROUND
  Sorafenib-everolimus combination therapy may be more effective than sorafenib monotherapy for hepatocellular carcinoma (HCC). To better understand this effect, we comparatively profiled the metabolite composition of HepG2 cells treated with sorafenib, everolimus, and sorafenib-everolimus combination therapy.
  
  
  METHODS
  A 2D HRMAS 1H-NMR metabolomic approach was applied to identify the key differential metabolites in 3 experimental groups: sorafenib (5 µM), everolimus (5 µM), and combination therapy (5 µM sorafenib +5 µM everolimus). MetaboAnalyst 3.0 was used to perform pathway analysis.
  
  
  RESULTS
  All OPLS-DA models displayed good separation between experimental groups, high-quality goodness of fit (R2), and high-quality goodness of predication (Q2). Sorafenib and everolimus have differential effects with respect to amino acid, methane, pyruvate, pyrimidine, aminoacyl-tRNA biosynthesis, and glycerophospholipid metabolism. The addition of everolimus to sorafenib resulted in differential effects with respect to pyruvate, amino acid, methane, glyoxylate and dicarboxylate, glycolysis or gluconeogenesis, glycerophospholipid, and purine metabolism.
  
  
  CONCLUSIONS
  Sorafenib and everolimus have differential effects on HepG2 cells. Sorafenib preferentially affects glycerophospholipid and purine metabolism, while the addition of everolimus preferentially affects pyruvate, amino acid, and glucose metabolism. This phenomenon may explain (in part) the synergistic effects of sorafenib-everolimus combination therapy observed in vivo.
authors.affiliation: The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China (mainland).
authors.forename: Jian-Feng
authors.initials: JF
authors.lastname: Zheng
authors.affiliation: Jiangxi Children's Hospital, Nanchang, Jiangxi, China (mainland).
authors.forename: Juan
authors.initials: J
authors.lastname: Lu
authors.affiliation: The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China (mainland).
authors.forename: Xiao-Zhong
authors.initials: XZ
authors.lastname: Wang
authors.affiliation: The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China (mainland).
authors.forename: Wu-Hua
authors.initials: WH
authors.lastname: Guo
authors.affiliation: The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China (mainland).
authors.forename: Ji-Xiang
authors.initials: JX
authors.lastname: Zhang
mesh_terms: D017304:Annexin A5; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D004357:Drug Synergism; D000068338:Everolimus / Q000494:pharmacology*; D016650:Fluorescein-5-isothiocyanate; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D053858:Metabolic Networks and Pathways / Q000187:drug effects*; D055432:Metabolomics / Q000379:methods; D015999:Multivariate Analysis; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D000077157:Sorafenib; D013778:Tetrazolium Salts; D013844:Thiazoles
chemical_list: D017304:Annexin A5; D010671:Phenylurea Compounds; D013778:Tetrazolium Salts; D013844:Thiazoles; D009536:Niacinamide; D000068338:Everolimus; D000077157:Sorafenib; C022616:thiazolyl blue; D016650:Fluorescein-5-isothiocyanate