The nitrobenzoxadiazole derivative MC3181 blocks melanoma invasion and metastasis

Anastasia De Luca, Debora Carpanese, Maria Cristina Rapanotti, Tara Mayte Suarez Viguria, Maria Antonietta Forgione, Dante Rotili, Chiara Fulci, Egidio Iorio, Luigi Quintieri, Sergio Chimenti, Luca Bianchi, Antonio Rosato, Anna Maria Caccuri

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)15520-15538
Number of pages19
JournalOncotarget
Volume8
Issue number9
DOIs
Publication statusPublished - Jan 1 2017

Keywords

  • 6-((7-nitrobenzo[c][1,2,5]oxadiazoles
  • Antimetastatic properties
  • C-Jun N-terminal kinase
  • Glutathione transferase P1-1
  • Melanoma

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    De Luca, A., Carpanese, D., Rapanotti, M. C., Suarez Viguria, T. M., Forgione, M. A., Rotili, D., Fulci, C., Iorio, E., Quintieri, L., Chimenti, S., Bianchi, L., Rosato, A., & Caccuri, A. M. (2017). The nitrobenzoxadiazole derivative MC3181 blocks melanoma invasion and metastasis. Oncotarget, 8(9), 15520-15538. https://doi.org/10.18632/oncotarget.14690