Inhibition of Hedgehog signalling by NVP-LDE225 (Erismodegib) interferes with growth and invasion of human renal cell carcinoma cells
| Autor: | Lucia Raimondo, Valentina D’Amato, Luigi Formisano, Franco Fulciniti, Lucia Nappi, R. Rosa, Roberto Bianco, S. De Placido, Cesar A. Bianco, Alberto Servetto, C. D'Amato, A Cipolletta, R. Marciano, Fortunato Ciardiello, Bianca Maria Veneziani, C. Di Mauro |
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| Přispěvatelé: | D'Amato, C., Rosa, R., Marciano, R., D'Amato, V., Formisano, L., Nappi, L., Raimondo, L., Di Mauro, C., Servetto, A., Fulciniti, F., Cipolletta, A., Bianco, C., Ciardiello, F., Veneziani, BIANCA MARIA, DE PLACIDO, Sabino, Bianco, Roberto, D'Amato, C, Rosa, R, Marciano, R, D'Amato, V, Formisano, L, Nappi, L, Raimondo, L, Di Mauro, C, Servetto, A, Fulciniti, F, Cipolletta, A, Bianco, C, Ciardiello, Fortunato, Veneziani, Bm, De Placido, S, Bianco, R. |
| Rok vydání: | 2014 |
| Předmět: |
Cancer Research
Indoles Lung Neoplasms Pyridines urologic and male genital diseases Receptors G-Protein-Coupled Mice sunitinib resistance Cell Movement immune system diseases Antineoplastic Combined Chemotherapy Protocols Sunitinib Mice Inbred BALB C Nuclear Proteins Ribosomal Protein S6 Kinases 70-kDa virus diseases Drug Synergism RCC Smoothened Receptor female genital diseases and pregnancy complications Kidney Neoplasms Tumor Burden Biphenyl compound Actin Cytoskeleton Oncology Neoplasm Micrometastasis Mitogen-Activated Protein Kinases Signal transduction Signal Transduction medicine.medical_specialty Kruppel-Like Transcription Factors NVP-LDE225 Mice Nude Zinc Finger Protein Gli2 Biology Zinc Finger Protein GLI1 Inhibitory Concentration 50 Cell Line Tumor Internal medicine Carcinoma medicine Animals Humans Hedgehog Proteins Pyrroles Everolimus Carcinoma Renal Cell Hedgehog Cell Proliferation Sirolimus Cell growth Biphenyl Compounds medicine.disease Actin cytoskeleton Xenograft Model Antitumor Assays Actins Endocrinology Cell culture Cancer research Hedgehog RCC NVP-LDE225 sunitinib resistance Paxillin Translational Therapeutics Proto-Oncogene Proteins c-akt Transcription Factors |
| Zdroj: | British Journal of Cancer |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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