title: A new water soluble MAPK activator exerts antitumor activity in melanoma cells resistant to the BRAF inhibitor vemurafenib.
abstract: Recovery of mitogen activated protein kinase (MAPK) or activation of alternative pathways, such as the PI3K/AKT/mTOR, are involved in acquired resistance to BRAF inhibitors which represent the first-line treatment of BRAF-mutated metastatic melanoma. We recently demonstrated that 6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio)hexan-1-ol (NBDHEX) and its water soluble analog 2-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio)ethoxy)ethoxy)ethanol (MC3181) trigger apoptosis in BRAF V600E mutated melanoma cells through activation of the MAPK c-Jun N-terminal kinase (JNK). Herein, we investigated whether NBDHEX and MC3181 might exert antitumor activity against BRAF V600E mutated human melanoma cells rendered resistant to the BRAF inhibitor vemurafenib. To this aim we generated a subline of A375 melanoma resistant in vitro and in vivo to vemurafenib (A375-VR8) and characterized by NRAS G13R mutation, high basal levels of CRAF protein and phospho-activation of AKT. In these cells ERK phosphorylation was not significantly down-modulated by vemurafenib concentrations capable of abrogating ERK phosphorylation in sensitive A375 cells. Both NBDHEX and MC3181 induced marked antiproliferative and apoptotic effects in A375-VR8 cells and, at equitoxic concentrations, caused a strong phosphorylation of JNK, p38, and of the downstream mediators of apoptosis ATF2 and p53. Drug treatment further increased ERK phosphorylation, which was required for the cellular response to the NBD derivatives, as apoptosis was antagonized by the ERK inhibitor FR180204. Finally, in vivo administration of MC3181 provoked JNK activation at the tumor site and markedly reduced A375-VR8 growth. These evidences strongly suggest that the activation of multiple pro-apoptotic MAPK pathways by MC3181 might represent a new strategy for the treatment of melanoma resistant to BRAF inhibitors.
authors: Department of Systems Medicine, University of "Tor Vergata", Rome, Italy.
authors: Grazia
authors: G
authors: Graziani
authors: Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, Rome, Italy.
authors: Simona
authors: S
authors: Artuso
authors: The NAST Centre for Nanoscience & Nanotechnology & Innovative Instrumentation, University of "Tor Vergata", Rome, Italy.
authors: Anastasia
authors: A
authors: De Luca
authors: Department of Systems Medicine, University of "Tor Vergata", Rome, Italy.
authors: Alessia
authors: A
authors: Muzi
authors: Department of Drug Chemistry and Technologies, "Sapienza" University, Rome, Italy.
authors: Dante
authors: D
authors: Rotili
authors: Department of Biomedicine and Prevention, University of "Tor Vergata", Rome, Italy; TMALab s.r.l., Spin-off of University of "Tor Vergata", Rome, Italy.
authors: Manuel
authors: M
authors: Scimeca
authors: Department of Systems Medicine, University of "Tor Vergata", Rome, Italy.
authors: Maria Grazia
authors: MG
authors: Atzori
authors: Department of Systems Medicine, University of "Tor Vergata", Rome, Italy.
authors: Claudia
authors: C
authors: Ceci
authors: Department of Drug Chemistry and Technologies, "Sapienza" University, Rome, Italy; Pasteur Institute, Cenci-Bolognetti Foundation, "Sapienza" University, Rome, Italy.
authors: Antonello
authors: A
authors: Mai
authors: Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, Rome, Italy.
authors: Carlo
authors: C
authors: Leonetti
authors: Laboratory of Molecular Oncology, "Istituto Dermopatico dell'Immacolata" - IRCCS, Rome, Italy.
authors: Lauretta
authors: L
authors: Levati
authors: Department of Biomedicine and Prevention, University of "Tor Vergata", Rome, Italy; TMALab s.r.l., Spin-off of University of "Tor Vergata", Rome, Italy.
authors: Elena
authors: E
authors: Bonanno
authors: Department of Systems Medicine, University of "Tor Vergata", Rome, Italy.
authors: Lucio
authors: L
authors: Tentori
authors: The NAST Centre for Nanoscience & Nanotechnology & Innovative Instrumentation, University of "Tor Vergata", Rome, Italy; Department of Experimental Medicine and Surgery, University of "Tor Vergata", Rome, Italy. Electronic address: caccuri@uniroma2.it.
authors: Anna Maria
authors: AM
authors: Caccuri
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D010069:Oxadiazoles / Q000494:pharmacology / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012995:Solubility; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D000077484:Vemurafenib; D014867:Water / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: C528479:6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol; D000970:Antineoplastic Agents; D007211:Indoles; D010069:Oxadiazoles; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D014867:Water; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF; Glutathione transferase; JNK; Melanoma; NBDHEX; Vemurafenib