Skip Navigation

Publication Detail

Title: Mefloquine induces ER stress and apoptosis in BRAFi-resistant A375-BRAFV600E /NRASQ61K malignant melanoma cells targeting intracranial tumors in a bioluminescent murine model.

Authors: Jandova, Jana; Park, Sophia L; Corenblum, Mandi J; Madhavan, Lalitha; Snell, Jeremy A; Rounds, Liliana; Wondrak, Georg T

Published In Mol Carcinog, (2022 Jun)

Abstract: Molecularly targeted therapeutics have revolutionized the treatment of BRAFV600E -driven malignant melanoma, but the rapid development of resistance to BRAF kinase inhibitors (BRAFi) presents a significant obstacle. The use of clinical antimalarials for the investigational treatment of malignant melanoma has shown only moderate promise, attributed mostly to inhibition of lysosomal-autophagic adaptations of cancer cells, but identification of specific antimalarials displaying single-agent antimelanoma activity has remained elusive. Here, we have screened a focused library of clinically used artemisinin-combination therapeutic (ACT) antimalarials for the apoptotic elimination of cultured malignant melanoma cell lines, also examining feasibility of overcoming BRAFi-resistance comparing isogenic melanoma cells that differ only by NRAS mutational status (BRAFi-sensitive A375-BRAFV600E /NRASQ61 vs. BRAFi-resistant A375-BRAFV600E /NRASQ61K ). Among ACT antimalarials tested, mefloquine (MQ) was the only apoptogenic agent causing melanoma cell death at low micromolar concentrations. Comparative gene expression-array analysis (A375-BRAFV600E /NRASQ61 vs. A375-BRAFV600E /NRASQ61K ) revealed that MQ is a dual inducer of endoplasmic reticulum (ER) and redox stress responses that precede MQ-induced loss of viability. ER-trackerTM DPX fluorescence imaging and electron microscopy indicated ER swelling, accompanied by rapid induction of ER stress signaling (phospho-eIF2α, XBP-1s, ATF4). Fluo-4 AM-fluorescence indicated the occurrence of cytosolic calcium overload observable within seconds of MQ exposure. In a bioluminescent murine model employing intracranial injection of A375-Luc2 (BRAFV600E /NRASQ61K ) cells, an oral MQ regimen efficiently antagonized brain tumor growth. Taken together, these data suggest that the clinical antimalarial MQ may be a valid candidate for drug repurposing aiming at chemotherapeutic elimination of malignant melanoma cells, even if metastasized to the brain and BRAFi-resistant.

PubMed ID: 35417045 Exiting the NIEHS site

MeSH Terms: Animals; Antimalarials*/pharmacology; Antimalarials*/therapeutic use; Apoptosis; Brain Neoplasms*/drug therapy; Cell Line, Tumor; Disease Models, Animal; Drug Resistance, Neoplasm/genetics; GTP Phosphohydrolases/genetics; Humans; Mefloquine/pharmacology; Mefloquine/therapeutic use; Melanoma*/drug therapy; Melanoma*/genetics; Melanoma*/pathology; Membrane Proteins/genetics; Mice; Protein Kinase Inhibitors/pharmacology; Proto-Oncogene Proteins B-raf; Skin Neoplasms

Back
to Top