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: Grazia Graziani, Simona Artuso, Anastasia De Luca, Alessia Muzi, Dante Rotili, Manuel Scimeca, Maria Grazia Atzori, Claudia Ceci, Antonello Mai, Carlo Leonetti, Lauretta Levati, Elena Bonanno, Lucio Tentori, Anna Maria Caccuri
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 95 Issue 1 Pg. 16-27 (May 01 2015) ISSN: 1873-2968 [Electronic] England
• PMID: 25795251 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol
• Antineoplastic Agents
• Indoles
• Oxadiazoles
• Protein Kinase Inhibitors
• Sulfonamides
• Water
• Vemurafenib
• BRAF protein, human
• Proto-Oncogene Proteins B-raf

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Drug Resistance, Neoplasm (drug effects, physiology)
• Enzyme Activation (drug effects, physiology)
• Humans
• Indoles (pharmacology, therapeutic use)
• MAP Kinase Signaling System (drug effects, physiology)
• Male
• Melanoma (drug therapy, metabolism)
• Mice
• Mice, Nude
• Oxadiazoles (pharmacology, therapeutic use)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Proto-Oncogene Proteins B-raf (antagonists & inhibitors, metabolism)
• Solubility
• Sulfonamides (pharmacology, therapeutic use)
• Vemurafenib
• Water (metabolism)
• Xenograft Model Antitumor Assays (methods)