title: The nitrobenzoxadiazole derivative MC3181 blocks melanoma invasion and metastasis.
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.
authors.affiliation: Department of Experimental Medicine and Surgery, University of Tor Vergata, 00133 Rome, Italy.
authors.forename: Anastasia
authors.initials: A
authors.lastname: De Luca
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy.
authors.forename: Debora
authors.initials: D
authors.lastname: Carpanese
authors.affiliation: Department of Laboratory Medicine, University of Tor Vergata, 00133 Rome, Italy.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Rapanotti
authors.affiliation: Department of Laboratory Medicine, University of Tor Vergata, 00133 Rome, Italy.
authors.forename: Tara Mayte Suarez
authors.initials: TM
authors.lastname: Viguria
authors.affiliation: Department of Drug Chemistry and Technologies, "Sapienza" University, 00185 Rome, Italy.
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Forgione
authors.affiliation: Department of Drug Chemistry and Technologies, "Sapienza" University, 00185 Rome, Italy.
authors.forename: Dante
authors.initials: D
authors.lastname: Rotili
authors.affiliation: Department of Experimental Medicine and Surgery, University of Tor Vergata, 00133 Rome, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Fulci
authors.affiliation: Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, 00161 Rome, Italy.
authors.forename: Egidio
authors.initials: E
authors.lastname: Iorio
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Quintieri
authors.affiliation: Department of Dermatology, University of Tor Vergata, 00133 Rome, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Chimenti
authors.affiliation: Department of Dermatology, University of Tor Vergata, 00133 Rome, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Bianchi
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy.|Istituto Oncologico Veneto IOV-IRCCS, 35128 Padova, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Rosato
authors.affiliation: Department of Experimental Medicine and Surgery, University of Tor Vergata, 00133 Rome, Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Caccuri
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D051929:CD146 Antigen / Q000235:genetics; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects* / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015151:Immunoblotting; D008175:Lung Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D009361:Neoplasm Invasiveness; D009578:Nitrobenzenes / Q000737:chemistry / Q000494:pharmacology*; D010069:Oxadiazoles / Q000737:chemistry / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051929:CD146 Antigen; C000622086:MC3181; D009578:Nitrobenzenes; D010069:Oxadiazoles; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020928:Mitogen-Activated Protein Kinases
keywords: 6-((7-nitrobenzo[c][1,2,5]oxadiazoles; antimetastatic properties; c-Jun N-terminal kinase; glutathione transferase P1-1; melanoma