title: Inhibition of Hedgehog signalling by NVP-LDE225 (Erismodegib) interferes with growth and invasion of human renal cell carcinoma cells.
abstract: BACKGROUND
  Multiple lines of evidence support that the Hedgehog (Hh) signalling has a role in the maintenance and progression of different human cancers. Therefore, inhibition of the Hh pathway represents a valid anticancer therapeutic approach for renal cell carcinoma (RCC) patients. NVP-LDE225 is a Smoothened (Smo) antagonist that induces dose-related inhibition of Hh and Smo-dependent tumour growth.
  
  
  METHODS
  We assayed the effects of NVP-LDE225 alone or in combination with everolimus or sunitinib on the growth and invasion of human RCC models both in vitro and in vivo. To this aim, we used a panel of human RCC models, comprising cells with acquired resistance to sunitinib - a multiple tyrosine kinase inhibitor approved as a first-line treatment for RCC.
  
  
  RESULTS
  NVP-LDE225 cooperated with either everolimus or sunitinib to inhibit proliferation, migration, and invasion of RCC cells even in sunitinib-resistant (SuR) cells. Some major transducers involved in tumour cell motility, including paxillin, were also efficiently inhibited by the combination therapy, as demonstrated by western blot and confocal microscopy assays. Moreover, these combined treatments inhibited tumour growth and increased animal survival in nude mice xenografted with SuR RCC cells. Finally, lung micrometastasis formation was reduced when mice were treated with NVP-LDE225 plus everolimus or sunitinib, as evidenced by artificial metastatic assays.
  
  
  CONCLUSIONS
  Hedgehog inhibition by NVP-LDE225 plus sunitinib or everolimus bolsters antitumour activity by interfering with tumour growth and metastatic spread, even in SuR cells. Thus, this new evidence puts forward a new promising therapeutic approach for RCC patients.
authors.affiliation: Cattedra di Oncologia Medica, Dipartimento di Medicina Clinica e Chirurgia, Università di Napoli "Federico II", Via S. Pansini 5, Napoli 80131, Italy.
authors.forename: C
authors.initials: C
authors.lastname: D'Amato
authors.affiliation: Cattedra di Oncologia Medica, Dipartimento di Medicina Clinica e Chirurgia, Università di Napoli "Federico II", Via S. Pansini 5, Napoli 80131, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Rosa
authors.affiliation: Cattedra di Oncologia Medica, Dipartimento di Medicina Clinica e Chirurgia, Università di Napoli "Federico II", Via S. Pansini 5, Napoli 80131, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Marciano
authors.affiliation: Cattedra di Oncologia Medica, Dipartimento di Medicina Clinica e Chirurgia, Università di Napoli "Federico II", Via S. Pansini 5, Napoli 80131, Italy.
authors.forename: V
authors.initials: V
authors.lastname: D'Amato
authors.affiliation: Cattedra di Oncologia Medica, Dipartimento di Medicina Clinica e Chirurgia, Università di Napoli "Federico II", Via S. Pansini 5, Napoli 80131, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Formisano
authors.affiliation: Cattedra di Oncologia Medica, Dipartimento di Medicina Clinica e Chirurgia, Università di Napoli "Federico II", Via S. Pansini 5, Napoli 80131, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Nappi
authors.affiliation: Cattedra di Oncologia Medica, Dipartimento di Medicina Clinica e Chirurgia, Università di Napoli "Federico II", Via S. Pansini 5, Napoli 80131, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Raimondo
authors.affiliation: Cattedra di Oncologia Medica, Dipartimento di Medicina Clinica e Chirurgia, Università di Napoli "Federico II", Via S. Pansini 5, Napoli 80131, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Di Mauro
authors.affiliation: Cattedra di Oncologia Medica, Dipartimento di Medicina Clinica e Chirurgia, Università di Napoli "Federico II", Via S. Pansini 5, Napoli 80131, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Servetto
authors.affiliation: Anatomia Patologica e Citopatologia, Istituto Nazionale Tumori 'Fondazione G. Pascale', IRCCS, Napoli 80131, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Fulciniti
authors.affiliation: Anatomia Patologica e Citopatologia, Istituto Nazionale Tumori 'Fondazione G. Pascale', IRCCS, Napoli 80131, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Cipolletta
authors.affiliation: Radioterapia, Istituto Nazionale Tumori 'Fondazione G. Pascale', IRCCS, Napoli 80131, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Bianco
authors.affiliation: Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale 'F. Magrassi e A. Lanzara', II Universitá degli Studi di Napoli, Napoli 80131, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Ciardiello
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II", Napoli 80131, Italy.
authors.forename: B M
authors.initials: BM
authors.lastname: Veneziani
authors.affiliation: Cattedra di Oncologia Medica, Dipartimento di Medicina Clinica e Chirurgia, Università di Napoli "Federico II", Via S. Pansini 5, Napoli 80131, Italy.
authors.forename: S
authors.initials: S
authors.lastname: De Placido
authors.affiliation: Cattedra di Oncologia Medica, Dipartimento di Medicina Clinica e Chirurgia, Università di Napoli "Federico II", Via S. Pansini 5, Napoli 80131, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Bianco
mesh_terms: D008841:Actin Cytoskeleton / Q000648:ultrastructure; D000199:Actins / Q000648:ultrastructure; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000008:administration & dosage; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000556:secondary; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D000068338:Everolimus; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D020128:Inhibitory Concentration 50; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D008175:Lung Neoplasms / Q000556:secondary*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D061206:Neoplasm Micrometastasis / Q000188:drug therapy; D009687:Nuclear Proteins / Q000378:metabolism; D051419:Paxillin / Q000378:metabolism / Q000648:ultrastructure; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011725:Pyridines / Q000008:administration & dosage; D011758:Pyrroles / Q000008:administration & dosage; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D000072086:Smoothened Receptor; D000077210:Sunitinib; D014157:Transcription Factors / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2
chemical_list: D000199:Actins; D001713:Biphenyl Compounds; C400551:GLI1 protein, human; C082593:GLI2 protein, human; D053823:Hedgehog Proteins; D007211:Indoles; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D051419:Paxillin; D011725:Pyridines; D011758:Pyrroles; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2; C561435:sonidegib; D000068338:Everolimus; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D020928:Mitogen-Activated Protein Kinases; D000077210:Sunitinib; D020123:Sirolimus
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