Mefloquine as a dual inhibitor of glioblastoma angiogenesis and glioblastoma via disrupting lysosomal function.

Angiogenesis, the formation of new blood vessels from the pre-existing ones, is a hallmark characteristic of glioblastoma, making it an appealing target for treatment development. Given potent anti-cancer efficacy of mefloquine, FDA-approved anti-malarial drug, there is increasing interest in repurposing mefloquine for treatment of cancers, including glioblastoma. In line with these efforts, our work is the first to demonstrate that mefloquine is also an inhibitor of glioblastoma angiogenesis. Using glioblastoma microvascular endothelial cell (GMEC) isolated from glioblastoma patients, we show that mefloquine at clinically achievable concentration inhibits GMEC differentiation, capillary network formation, adhesion to Matrix, growth and survival. Mefloquine also inhibits growth and induces apoptosis in glioblastoma cells regardless of cellular origin and genetic background. We further show that mefloquine significantly inhibits glioblastoma growth but not formation, and this is associated with decreased glioblastoma angiogenesis in mice. Mechanistically, mefloquine disrupted lysosomal integrity and function in GMECs, leading to oxidative stress and lysosomal lipid damage. Rescue studies confirm that mefloquine acts on GMECs in a lysosomal disruption-dependent manner. Our findings demonstrate the anti-angiogenic activity of mefloquine via disrupting lysosomal function. The dual inhibitory role of mefloquine in glioblastoma angiogenesis and glioblastoma displays its advantage over other anti-cancer drugs for glioblastoma treatment. Our work also highlights the essential role of lysosome in both glioblastoma and its angiogenesis.