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.

De Luca, A., Carpanese, D., Rapanotti, M.c., Suarez Viguria, T.m., Forgione, M.a., Rotili, D., et al. (2017). The nitrobenzoxadiazole derivative MC3181 blocks melanoma invasion and metastasis. ONCOTARGET, 8(9), 15520-15538 [10.18632/oncotarget.14690].

The nitrobenzoxadiazole derivative MC3181 blocks melanoma invasion and metastasis

De Luca A.;Fulci C.;Iorio E.;Bianchi L.;Caccuri A. M.
2017-01-01

Abstract

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.
2017
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore MED/35 - MALATTIE CUTANEE E VENEREE
Settore BIO/10 - BIOCHIMICA
English
Con Impact Factor ISI
melanoma
6-((7-nitrobenzo[c][1,2,5] oxadiazoles
c-Jun N-terminal kinase
antimetastatic properties
glutathione transferase P1-1
Animals
Antineoplastic Agents
CD146 Antigen
Cell Culture Techniques
Cell Line, Tumor
Cell Movement
Cell Proliferation
Cell Survival
Gene Expression Regulation, Neoplastic
Humans
Immunoblotting
Lung Neoplasms
Melanoma
Melanoma, Experimental
Mice
Mitogen-Activated Protein Kinases
Mutation
Neoplasm Invasiveness
Nitrobenzenes
Oxadiazoles
Proto-Oncogene Proteins B-raf
Reverse Transcriptase Polymerase Chain Reaction
Skin Neoplasms
Spheroids, Cellular
De Luca, A., Carpanese, D., Rapanotti, M.c., Suarez Viguria, T.m., Forgione, M.a., Rotili, D., et al. (2017). The nitrobenzoxadiazole derivative MC3181 blocks melanoma invasion and metastasis. ONCOTARGET, 8(9), 15520-15538 [10.18632/oncotarget.14690].
De Luca, A; Carpanese, D; Rapanotti, Mc; Suarez Viguria, Tm; Forgione, Ma; Rotili, D; Fulci, C; Iorio, E; Quintieri, L; Chimenti, S; Bianchi, L; Rosato, A; Caccuri, Am
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/284684
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