The nitrobenzoxadiazole derivative MC3181 blocks melanoma invasion and metastasis

A. De Luca, D. Carpanese, M.C. Rapanotti, T.M. Suarez Viguria, M.A. Forgione, D. Rotili, C. Fulci, E. Iorio, L. Quintieri, S. Chimenti, L. Bianchi, A. Rosato, A.M. Caccuri

Research output: Contribution to journalArticlepeer-review


The novel nitrobenzoxadiazole (NBD) derivative MC3181 is endowed with remarkable therapeutic activity in mice bearing both sensitive and vemurafenibresistant 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.
Original languageEnglish
Pages (from-to)15520-15538
Number of pages19
Issue number9
Publication statusPublished - 2017


  • 6-((7-nitrobenzo[c][1,2,5]oxadiazoles
  • Antimetastatic properties
  • C-Jun N-terminal kinase
  • Glutathione transferase P1-1
  • Melanoma
  • 2 [2 [2 [(7 nitrobenzo[c][1,2,5]oxadiazol 4 yl)thio]ethoxy]ethoxy]ethanol
  • antineoplastic agent
  • aspartic acid
  • B Raf kinase
  • CD146 antigen
  • gelatinase A
  • lactic acid
  • mitogen activated protein kinase
  • nerve cell adhesion molecule
  • stress activated protein kinase
  • temozolomide
  • transcription factor AP 2
  • unclassified drug
  • valine
  • vasculotropin
  • vemurafenib
  • BRAF protein, human
  • MC3181
  • nitrobenzene derivative
  • oxadiazole derivative
  • animal experiment
  • animal model
  • animal tissue
  • Article
  • biosynthesis
  • cancer inhibition
  • cancer patient
  • cancer survival
  • cell count
  • concentration response
  • controlled study
  • drug mechanism
  • enzyme activation
  • glycolysis
  • human
  • human cell
  • in vivo study
  • lung metastasis
  • male
  • melanoma
  • melanoma cell line
  • metastasis inhibition
  • monolayer culture
  • mouse
  • nonhuman
  • protein expression
  • tumor invasion
  • tumor spheroid
  • tumor vascularization
  • WM115 cell line
  • WM266.4 cell line
  • animal
  • cell culture technique
  • cell motion
  • cell proliferation
  • cell survival
  • chemistry
  • drug effects
  • gene expression regulation
  • genetics
  • immunoblotting
  • Lung Neoplasms
  • Melanoma, Experimental
  • metabolism
  • multicellular spheroid
  • mutation
  • pathology
  • reverse transcription polymerase chain reaction
  • secondary
  • skin tumor
  • tumor cell line
  • Animals
  • Antigens, CD146
  • Antineoplastic Agents
  • Cell Culture Techniques
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Cell Survival
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunoblotting
  • Mice
  • Mitogen-Activated Protein Kinases
  • Mutation
  • Neoplasm Invasiveness
  • Nitrobenzenes
  • Oxadiazoles
  • Proto-Oncogene Proteins B-raf
  • Reverse Transcriptase Polymerase Chain Reaction
  • Skin Neoplasms
  • Spheroids, Cellular

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