title: Synergistic cooperation between sunitinib and cisplatin promotes apoptotic cell death in human medullary thyroid cancer.
abstract: BACKGROUND
  Tyrosine kinase inhibitors represent a new treatment option for patients with advanced medullary thyroid cancer (MTC). However, cures have not been achieved with current available agents used in monotherapy.
  
  
  OBJECTIVE
  Because RET has been shown to negatively regulate CD95 death receptor activation in preclinical models of RET-dependent MTC, we investigated the potential of the combination approach with the RET-targeting tyrosine kinase inhibitor sunitinib and cisplatin to enhance apoptosis activation through the extrinsic pathway.
  
  
  METHODS
  The effects of sunitinib and cisplatin were examined in human MTC cell lines harboring oncogenic RET mutations. Experiments were designed to determine drug effects on RET signaling, cell growth, apoptosis, autophagy, and tumor growth in mice and to investigate the mechanisms of the drug interaction.
  
  
  RESULTS
  Sunitinib and cisplatin synergistically inhibited the growth of MZ-CRC-1 cells harboring the RET M918T activating mutation. The combination enhanced apoptosis activation through CD95-mediated, caspase-8-dependent pathway. Moreover, sunitinib induced a severe perturbation of the autophagic flux characterized by autophagosome accumulation and a remarkable lysosomal dysfunction, which was further enhanced, with lysosomal leakage induction, by cisplatin. Administration of the drug combination to mice xenografted with MZ-CRC-1 cells improved the antitumor efficacy, as compared with single-agent treatments, inducing complete responses in 30% of the treated mice, a significant increase in caspase-3 activation (P < .01 vs cisplatin, and P < .0005 vs sunitinib) and apoptosis in tumor cells.
  
  
  CONCLUSIONS
  Addition of cisplatin to sunitinib potentiates apoptotic cell death and has promising preclinical activity in MTCs harboring the RET M918T oncogene.
authors.affiliation: Molecular Pharmacology Unit (A.L., V.N., E.F., L.D.B., M.T., D.C., M.F., P.P., N.Z., G.C., C.L.) and Molecular Mechanisms Unit (M.G.B.), Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy; Department of Veterinary Sciences and Public Health (V.C., E.S.), Università degli Studi di Milano, 20133 Milan, Italy; and Mouse and Animal Pathology Laboratory (V.C., E.S.), Fondazione Filarete, 20139 Milan, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Lopergolo
authors.forename: Valentina
authors.initials: V
authors.lastname: Nicolini
authors.forename: Enrica
authors.initials: E
authors.lastname: Favini
authors.forename: Laura
authors.initials: L
authors.lastname: Dal Bo
authors.forename: Monica
authors.initials: M
authors.lastname: Tortoreto
authors.forename: Denis
authors.initials: D
authors.lastname: Cominetti
authors.forename: Marco
authors.initials: M
authors.lastname: Folini
authors.forename: Paola
authors.initials: P
authors.lastname: Perego
authors.forename: Vittoria
authors.initials: V
authors.lastname: Castiglioni
authors.forename: Eugenio
authors.initials: E
authors.lastname: Scanziani
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Borrello
authors.forename: Nadia
authors.initials: N
authors.lastname: Zaffaroni
authors.forename: Giuliana
authors.initials: G
authors.lastname: Cassinelli
authors.forename: Cinzia
authors.initials: C
authors.lastname: Lanzi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D018276:Carcinoma, Medullary / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology* / Q000627:therapeutic use; D004357:Drug Synergism; D006801:Humans; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D000077210:Sunitinib; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D002945:Cisplatin; D000077210:Sunitinib