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

English version

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

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

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