NVP-LDE225, a potent and selective SMOOTHENED antagonist reduces melanoma growth in vitro and in vivo.
Melanoma is one of the most aggressive cancers and its incidence is increasing worldwide. So far there are no curable therapies especially after metastasis. Due to frequent mutations in members of the mitogen-activated protein kinase (MAPK) signaling pathway, this pathway is constitutively active in melanoma. It has been shown that the SONIC HEDGEHOG (SHH)-GLI and MAPK signaling pathway regulate cell growth in many tumors including melanoma and interact with each other in the regulation of cell proliferation and survival. Here we show that the SHH-GLI pathway is active in human melanoma cell lines as they express downstream target of this pathway GLI1. Expression of GLI1 was significantly higher in human primary melanoma tissues harboring BRAF(V600E) mutation than those with wild type BRAF. Pharmacologic inhibition of BRAF(V600E) in human melanoma cell lines resulted in decreased expression of GLI1 thus demonstrating interaction of SHH-GLI and MAPK pathways. Inhibition of SHH-GLI pathway by the novel small molecule inhibitor of smoothened NVP-LDE225 was followed by inhibition of cell growth and induction of apoptosis in human melanoma cell lines, interestingly with both BRAF(V600E) and BRAF(Wild Type) status. NVP-LDE225 was potent in reducing cell proliferation and inducing tumor growth arrest in vitro and in vivo, respectively and these effects were superior to the natural compound cyclopamine. Finally, we conclude that inhibition of SHH-GLI signaling pathway in human melanoma by the specific smoothened inhibitor NVP-LDE225 could have potential therapeutic application in human melanoma even in the absence of BRAF(V600E) mutation and warrants further investigations.
Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, Vienna, Austria. ahmad.jalili@meduniwien.ac.at
Ahmad
A
Jalili
Kirsten D
KD
Mertz
Julia
J
Romanov
Christine
C
Wagner
Frank
F
Kalthoff
Anton
A
Stuetz
Gaurav
G
Pathria
Melanie
M
Gschaider
Georg
G
Stingl
Stephan N
SN
Wagner
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000072086:Smoothened Receptor; D013449:Sulfonamides / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D000077484:Vemurafenib; D023041:Xenograft Model Antitumor Assays; D000071676:Zinc Finger Protein GLI1
D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; C400551:GLI1 protein, human; D053823:Hedgehog Proteins; D007211:Indoles; D011725:Pyridines; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor; D013449:Sulfonamides; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; C561435:sonidegib; D000077484:Vemurafenib; D048493:Proto-Oncogene Proteins B-raf