Inhibition of Hedgehog signalling by NVP-LDE225 (Erismodegib) interferes with growth and invasion of human renal cell carcinoma cells

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 Smoothene...

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Bibliographic Details
Published in:British journal of cancer 2014-09, Vol.111 (6), p.1168-1179
Main Authors: D'AMATO, C, ROSA, R, CIPOLLETTA, A, BIANCO, C, CIARDIELLO, F, VENEZIANI, B. M, DE PLACIDO, S, BIANCO, R, MARCIANO, R, D'AMATO, V, FORMISANO, L, NAPPI, L, RAIMONDO, L, DI MAURO, C, SERVETTO, A, FULCINITI, F
Format: Article
Language:English
Subjects:
Actin Cytoskeleton - ultrastructure
Actins - ultrastructure
Animals
Antineoplastic Combined Chemotherapy Protocols - administration & dosage
Antineoplastic Combined Chemotherapy Protocols - pharmacology
Biological and medical sciences
Biphenyl Compounds - administration & dosage
Cancer therapies
Carcinoma, Renal Cell - drug therapy
Carcinoma, Renal Cell - secondary
Cell growth
Cell Line, Tumor
Cell Movement - drug effects
Cell Proliferation - drug effects
Drug Synergism
Everolimus
Genes
Hedgehog Proteins - metabolism
Humans
Hypoxia
Indoles - administration & dosage
Inhibitory Concentration 50
Kidney cancer
Kidney Neoplasms - drug therapy
Kidney Neoplasms - pathology
Kidneys
Kinases
Kruppel-Like Transcription Factors - metabolism
Ligands
Lung Neoplasms - secondary
Medical sciences
Metastasis
Mice
Mice, Inbred BALB C
Mice, Nude
Mitogen-Activated Protein Kinases - metabolism
Multiple tumors. Solid tumors. Tumors in childhood (general aspects)
Neoplasm Micrometastasis - drug therapy
Nephrology. Urinary tract diseases
Nuclear Proteins - metabolism
Paxillin - metabolism
Paxillin - ultrastructure
Proto-Oncogene Proteins c-akt - metabolism
Pyridines - administration & dosage
Pyrroles - administration & dosage
Receptors, G-Protein-Coupled - antagonists & inhibitors
Receptors, G-Protein-Coupled - metabolism
Ribosomal Protein S6 Kinases, 70-kDa - metabolism
Signal Transduction - drug effects
Sirolimus - administration & dosage
Sirolimus - analogs & derivatives
Smoothened Receptor
Transcription Factors - metabolism
Translational Therapeutics
Tumor Burden - drug effects
Tumors
Tumors of the urinary system
Vascular endothelial growth factor
Xenograft Model Antitumor Assays
Zinc Finger Protein GLI1
Zinc Finger Protein Gli2
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Summary: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. 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. 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. 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.
ISSN:0007-0920
1532-1827
DOI:10.1038/bjc.2014.421