Lumefantrine, an antimalarial drug, reverses radiation and temozolomide resistance in glioblastoma
Menée in vitro et à l'aide d'un modèle murin, cette étude met en évidence l'intérêt de la luméfrantine, un antipaludique, pour lever la résistance des glioblastomes au témozolomide et aux rayonnements ionisants
No current therapies prevent recurrence in patients with glioblastoma multiforme (GBM). Extracellular matrix (ECM) remodeling and epithelial mesenchymal transition (EMT) are important processes regulating GBM progression and acquisition of radiation and temozolomide (radio/TMZ) resistance. Fli-1 choreographs ECM remodeling and EMT in GBM via transcriptional regulation of HSPB1. Lumefantrine, an antimalarial drug, inhibits the transcriptional activities of Fli-1 and its downstream targets HSPB1, ECM remodeling, and EMT. Lumefantrine is selectively cytotoxic and promotes apoptosis in GBM and reverses radio/TMZ resistance in GBM. This drug can easily be repurposed for management of GBM. Identification of drugs like lumefantrine from FDA-approved therapeutic agents and uncommon sources provides opportunities to broaden the breadth and versatility of current therapeutic regimens for GBM.Glioblastoma multiforme (GBM) is an aggressive cancer without currently effective therapies. Radiation and temozolomide (radio/TMZ) resistance are major contributors to cancer recurrence and failed GBM therapy. Heat shock proteins (HSPs), through regulation of extracellular matrix (ECM) remodeling and epithelial mesenchymal transition (EMT), provide mechanistic pathways contributing to the development of GBM and radio/TMZ-resistant GBM. The Friend leukemia integration 1 (Fli-1) signaling network has been implicated in oncogenesis in GBM, making it an appealing target for advancing novel therapeutics. Fli-1 is linked to oncogenic transformation with up-regulation in radio/TMZ-resistant GBM, transcriptionally regulating HSPB1. This link led us to search for targeted molecules that inhibit Fli-1. Expression screening for Fli-1 inhibitors identified lumefantrine, an antimalarial drug, as a probable Fli-1 inhibitor. Docking and isothermal calorimetry titration confirmed interaction between lumefantrine and Fli-1. Lumefantrine promoted growth suppression and apoptosis in vitro in parental and radio/TMZ-resistant GBM and inhibited tumor growth without toxicity in vivo in U87MG GBM and radio/TMZ-resistant GBM orthotopic tumor models. These data reveal that lumefantrine, an FDA-approved drug, represents a potential GBM therapeutic that functions through inhibition of the Fli-1/HSPB1/EMT/ECM remodeling protein networks.