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Nilotinib, an approved leukemia drug, inhibits smoothened signaling in Hedgehog-dependent medulloblastoma


Autoři: Kirti Kandhwal Chahal aff001;  Jie Li aff003;  Irina Kufareva aff001;  Milind Parle aff002;  Donald L. Durden aff004;  Robert J. Wechsler-Reya aff005;  Clark C. Chen aff003;  Ruben Abagyan aff001
Působiště autorů: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego (UCSD), La Jolla, California, United States of America aff001;  Department of Pharmaceutical Sciences, G.J. University of Science and Technology, Hisar, India aff002;  Department of Neurosurgery, Minneapolis, Minnesota, United States of America aff003;  Department of Pediatrics, Moores Cancer Center, School of Medicine, UCSD and Rady Children’s Hospital, San Diego, La Jolla, California, United States of America aff004;  Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, United States of America aff005
Vyšlo v časopise: PLoS ONE 14(9)
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pone.0214901

Souhrn

Dysregulation of the seven-transmembrane (7TM) receptor Smoothened (SMO) and other components of the Hedgehog (Hh) signaling pathway contributes to the development of cancers including basal cell carcinoma (BCC) and medulloblastoma (MB). However, SMO-specific antagonists produced mixed results in clinical trials, marked by limited efficacy and high rate of acquired resistance in tumors. Here we discovered that Nilotinib, an approved inhibitor of several kinases, possesses an anti-Hh activity, at clinically achievable concentrations, due to direct binding to SMO and inhibition of SMO signaling. Nilotinib was more efficacious than the SMO-specific antagonist Vismodegib in inhibiting growth of two Hh-dependent MB cell lines. It also reduced tumor growth in subcutaneous MB mouse xenograft model. These results indicate that in addition to its known activity against several tyrosine-kinase-mediated proliferative pathways, Nilotinib is a direct inhibitor of the Hh pathway. The newly discovered extension of Nilotinib’s target profile holds promise for the treatment of Hh-dependent cancers.

Klíčová slova:

Biology and life sciences – Cell biology – Research and analysis methods – Medicine and health sciences – Cellular structures and organelles – Pharmacology – Oncology – Cancer treatment – Cancers and neoplasms – Cell membranes – Signal transduction – Bioassays and physiological analysis – Cell signaling – Chemical characterization – Binding analysis – Blastomas – Hedgehog signaling – Cell analysis – Cell viability testing – Medulloblastoma – Drug screening – Fluorescence competition


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