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Structural Bioinformatics and Protein Docking Analysis of the Molecular Chaperone-Kinase Interactions: Towards Allosteric Inhibition of Protein Kinases by Targeting the Hsp90-Cdc37 Chaperone Machinery
Pharmaceuticals 2013, 6(11), 1429-1450; doi:10.3390/ph6111429

Hedgehog Pathway Blockade Inhibits Melanoma Cell Growth in Vitro and in Vivo

Received: 3 September 2013 / Revised: 24 October 2013 / Accepted: 31 October 2013 / Published: 11 November 2013
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Previous reports have demonstrated a role for hedgehog signaling in melanoma progression, prompting us to explore the therapeutic benefit of targeting this pathway in melanoma. We profiled a panel of human melanoma cell lines and control melanocytes for altered expression of hedgehog pathway members and determined the consequences of both genetic and pharmacological inhibition of the hedgehog pathway activator Smoothened (SMO) in melanoma, both in vitro and in vivo. We also examined the relationship between altered expression of hedgehog pathway mediators and survival in a well-characterized cohort of metastatic melanoma patients with prospectively collected follow up information. Studies revealed that over 40% of the melanoma cell lines examined harbored significantly elevated levels of the hedgehog pathway mediators SMO, GLI2, and PTCH1 compared to melanocytes (p < 0.05). SMO inhibition using siRNA and the small molecule inhibitor, NVP-LDE-225, suppressed melanoma growth in vitro, particularly in those cell lines with moderate SMO and GLI2 expression. NVP-LDE-225 also induced apoptosis in vitro and inhibited melanoma growth in a xenograft model. Gene expression data also revealed evidence of compensatory up-regulation of two other developmental pathways, Notch and WNT, in response to hedgehog pathway inhibition. Pharmacological and genetic SMO inhibition also downregulated genes involved in human embryonic stem cell pluripotency. Finally, increased SMO expression and decreased expression of the hedgehog pathway repressor GLI3 correlated with shorter post recurrence survival in metastatic melanoma patients. Our data demonstrate that hedgehog pathway inhibition might be a promising targeted therapy in appropriately selected metastatic melanoma patients.
Keywords: melanoma; hedgehog; Smoothened; GLI2; PTCH1 melanoma; hedgehog; Smoothened; GLI2; PTCH1
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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O'Reilly, K.E.; de Miera, E.V.-S.; Segura, M.F.; Friedman, E.; Poliseno, L.; Han, S.W.; Zhong, J.; Zavadil, J.; Pavlick, A.; Hernando, E.; Osman, I. Hedgehog Pathway Blockade Inhibits Melanoma Cell Growth in Vitro and in Vivo. Pharmaceuticals 2013, 6, 1429-1450.

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