Research Papers:
The nitrobenzoxadiazole derivative MC3181 blocks melanoma invasion and metastasis
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Abstract
Anastasia De Luca1,*, Debora Carpanese2,*, Maria Cristina Rapanotti3, Tara Mayte Suarez Viguria3, Maria Antonietta Forgione4, Dante Rotili4, Chiara Fulci1, Egidio Iorio5, Luigi Quintieri6, Sergio Chimenti7, Luca Bianchi7, Antonio Rosato2,8, Anna Maria Caccuri1
1Department of Experimental Medicine and Surgery, University of Tor Vergata, 00133 Rome, Italy
2Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy
3Department of Laboratory Medicine, University of Tor Vergata, 00133 Rome, Italy
4Department of Drug Chemistry and Technologies, “Sapienza” University, 00185 Rome, Italy
5Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, 00161 Rome, Italy
6Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy
7Department of Dermatology, University of Tor Vergata, 00133 Rome, Italy
8Istituto Oncologico Veneto IOV-IRCCS, 35128 Padova, Italy
*These authors have contributed equally to this work
Correspondence to:
Anna Maria Caccuri, email: [email protected]
Antonio Rosato, email: [email protected]
Keywords: melanoma, 6-((7-nitrobenzo[c][1,2,5]oxadiazoles, c-Jun N-terminal kinase, antimetastatic properties, glutathione transferase P1-1
Received: July 25, 2016 Accepted: December 27, 2016 Published: January 17, 2017
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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