A new water soluble MAPK activator exerts antitumor activity in melanoma cells resistant to the BRAF inhibitor vemurafenib

Biochemical Pharmacology
Grazia GrazianiAnna Maria Caccuri

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 ...Continue Reading

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Citations

Feb 6, 2016·Journal of Translational Medicine·Camilla PalumboAnna Maria Caccuri
Nov 24, 2016·Nutrients·Claudia CeciGrazia Graziani
Feb 12, 2019·Journal of Cellular Physiology·Francesca SciarrettaAnna Maria Caccuri
Dec 5, 2019·Mutagenesis·Kerstin HuebnerRegine Schneider-Stock
Jan 21, 2017·Oncotarget·Anastasia De LucaAnna Maria Caccuri
Jan 24, 2018·Bioscience Reports·Huan-Huan ShaJi-Feng Feng
Jul 17, 2018·Cancer Biomarkers : Section a of Disease Markers·Xiaohui WangLinxia Zhang
May 7, 2019·Frontiers in Oncology·Stephen A Luebker, Scott A Koepsell
Feb 12, 2021·Journal of Medicinal Chemistry·Ross S ManciniMark A Reed
Jun 1, 2020·Biochemical Pharmacology·Veronica Di PaoloAnna Maria Caccuri
Mar 5, 2019·Chemical Research in Toxicology·Seyyede Araste Aldaghi, Razieh Jalal
Sep 30, 2021·Journal of Enzyme Inhibition and Medicinal Chemistry·Francesco FiorentinoAntonello Mai

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