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Mefloquine induces ER stress and apoptosis in BRAFi-resistant A375-BRAFV600E/NRASQ61K malignant melanoma cells targeting intracranial tumors in a bioluminescent murine model
Molecular Carcinogenesis ( IF 3.0 ) Pub Date : 2022-04-13 , DOI: 10.1002/mc.23407
Jana Jandova 1 , Sophia L Park 1 , Mandi J Corenblum 2 , Lalitha Madhavan 2 , Jeremy A Snell 1 , Liliana Rounds 1 , Georg T Wondrak 1
Affiliation  

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.

中文翻译:


甲氟喹在生物发光小鼠模型中诱导针对颅内肿瘤的 BRAFi 耐药 A375-BRAFV600E/NRASQ61K 恶性黑色素瘤细胞的 ER 应激和细胞凋亡



分子靶向治疗彻底改变了 BRAF V600E驱动的恶性黑色素瘤的治疗,但 BRAF 激酶抑制剂 (BRAFi) 耐药性的快速发展提出了重大障碍。临床抗疟药用于恶性黑色素瘤研究性治疗的应用仅显示出有限的前景,这主要归因于抑制癌细胞的溶酶体自噬适应,但表现出单药抗黑色素瘤活性的特定抗疟药的鉴定仍然难以捉摸。在这里,我们筛选了临床使用的青蒿素联合治疗 (ACT) 抗疟药的重点库,用于消除培养的恶性黑色素瘤细胞系的凋亡,还比较了仅因 NRAS 突变状态而不同的同基因黑色素瘤细胞,研究了克服 BRAFi 耐药性的可行性。 BRAFi 敏感 A375-BRAF V600E /NRAS Q61与 BRAFi 抗性 A375-BRAF V600E /NRAS Q61K )。在测试的 ACT 抗疟药中,甲氟喹 (MQ) 是唯一一种在低微摩尔浓度下导致黑色素瘤细胞死亡的凋亡剂。比较基因表达阵列分析(A375-BRAF V600E /NRAS Q61与 A375-BRAF V600E /NRAS Q61K )表明,MQ 是内质网 (ER) 和氧化还原应激反应的双重诱导剂,该反应先于 MQ 诱导的活力丧失。 ER-tracker TM DPX 荧光成像和电子显微镜显示内质网肿胀,并伴有内质网应激信号(磷酸化 eIF2α、XBP-1s、ATF4)的快速诱导。 Fluo-4 AM 荧光表明在 MQ 暴露后数秒内可观察到细胞质钙超载的发生。 在采用颅内注射 A375-Luc2 (BRAF V600E /NRAS Q61K ) 细胞的生物发光小鼠模型中,口服 MQ 方案可有效拮抗脑肿瘤生长。总而言之,这些数据表明,临床抗疟药 MQ 可能是药物再利用的有效候选药物,旨在通过化疗消除恶性黑色素瘤细胞,即使其已转移至大脑且对 BRAFi 耐药。
更新日期:2022-04-13
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