lde225 and Kidney-Neoplasms

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.

Topics: Actin Cytoskeleton; Actins; Animals; Antineoplastic Combined Chemotherapy Protocols; Biphenyl Compounds; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Movement; Cell Proliferation; Drug Synergism; Everolimus; Hedgehog Proteins; Humans; Indoles; Inhibitory Concentration 50; Kidney Neoplasms; Kruppel-Like Transcription Factors; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Mitogen-Activated Protein Kinases; Neoplasm Micrometastasis; Nuclear Proteins; Paxillin; Proto-Oncogene Proteins c-akt; Pyridines; Pyrroles; Receptors, G-Protein-Coupled; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sirolimus; Smoothened Receptor; Sunitinib; Transcription Factors; Tumor Burden; Xenograft Model Antitumor Assays; Zinc Finger Protein GLI1; Zinc Finger Protein Gli2