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The nitrobenzoxadiazole derivative MC3181 blocks melanoma invasion and metastasis.

Authors
  • De Luca, Anastasia1
  • Carpanese, Debora2
  • Rapanotti, Maria Cristina3
  • Viguria, Tara Mayte Suarez3
  • Forgione, Maria Antonietta4
  • Rotili, Dante4
  • Fulci, Chiara1
  • Iorio, Egidio5
  • Quintieri, Luigi6
  • Chimenti, Sergio7
  • Bianchi, Luca7
  • Rosato, Antonio2, 8
  • Caccuri, Anna Maria1
  • 1 Department of Experimental Medicine and Surgery, University of Tor Vergata, 00133 Rome, Italy. , (Italy)
  • 2 Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy. , (Italy)
  • 3 Department of Laboratory Medicine, University of Tor Vergata, 00133 Rome, Italy. , (Italy)
  • 4 Department of Drug Chemistry and Technologies, "Sapienza" University, 00185 Rome, Italy. , (Italy)
  • 5 Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, 00161 Rome, Italy. , (Italy)
  • 6 Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy. , (Italy)
  • 7 Department of Dermatology, University of Tor Vergata, 00133 Rome, Italy. , (Italy)
  • 8 Istituto Oncologico Veneto IOV-IRCCS, 35128 Padova, Italy. , (Italy)
Type
Published Article
Journal
Oncotarget
Publisher
"Impact Journals, LLC "
Publication Date
Feb 28, 2017
Volume
8
Issue
9
Pages
15520–15538
Identifiers
DOI: 10.18632/oncotarget.14690
PMID: 28107182
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

The novel nitrobenzoxadiazole (NBD) derivative MC3181 is endowed with remarkable therapeutic activity in mice bearing both sensitive and vemurafenib-resistant human melanoma xenografts. Here, we report that subtoxic concentrations of this compound significantly reduced invasiveness of BRAF-V600D mutated WM115 and WM266.4 melanoma cell lines derived from the primary lesion and related skin metastasis of the same patient, respectively. The strong antimetastatic activity of MC3181 was observed in both 2D monolayer cultures and 3D multicellular tumor spheroids, and confirmed in vivo by the significant decrease in the number of B16-F10 melanoma lung metastases in drug-treated mice. Our data also show that MC3181 affects the lactate production in the high glycolytic WM266.4 cell line. To unveil the MC3181 mechanism of action, we analyzed the ability of MC3181 to affect the degree of activation of different MAPK pathways, as well as the expression/activity levels of several proteins involved in angiogenesis, invasion, and survival (i.e. AP2, MCAM/MUC18, N-cadherin, VEGF and MMP-2). Our data disclosed both a decrease of the phospho-active form of JNK and an increased expression of the transcription factor AP2, events that occur in the very early phase of drug treatment and may be responsible of the antimetastatic effects of MC3181.

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