Abstract Medulloblastomas (MB) are the most common malignant pediatric brain tumor, with group 3 tumors (G3MB) being the most aggressive. Uniquely, their aggressiveness is inversely related to the activation of ferroptosis, a form of programmed cell death mediated by iron overload. Instead, these aggressive tumors activate iron-sulfur (Fe-S) cluster binding, inhibit reactive oxygen species (ROS) generation, and upregulate the expression of glutathione peroxidase 4 (GPX4), the central regulator of ferroptosis. Our main objective was to investigate whether ferroptosis evasion was a targetable driver of aggressiveness in G3MBs and whether targeting this driver could potentiate classical chemotherapy. We hypothesized that inhibiting Fe-S cluster export by targeting ABCB7, the principal mitochondrial Fe-S exporter, would induce iron overload, trigger ferroptosis, and ultimately potentiate cisplatin cytotoxicity in G3MBs. Silencing ABCB7 (si-/sh-/KO) in classical G3MB cell lines (HDMB03 and D425) resulted in mitochondrial iron overload, oxidative stress, and lipid ROS, culminating in growth retardation. It also accelerated erastin-induced ferroptosis. Seahorse studies revealed a switch from oxidative phosphorylation to glycolysis, and TMRM staining revealed loss of mitochondrial membrane potential. Notably, silencing ABCB7 abrogated GPX4 expression and reduced GSH levels. It also halved the IC50 of cisplatin, with ABCB7-silenced cells treated with cisplatin experiencing accelerated ferroptosis. Silencing ABCB7 in vivo mitigated tumor burden by activating ferroptosis and potentiated cisplatin action. We further investigated the impact of pharmacologic inhibition of ABCB7 by artesunate, an FDA-approved, blood-brain barrier-penetrant, anti-malarial drug capable of inducing iron overload, on G3MB tumor burden and cisplatin action. Artesunate potentiated cisplatin action in vitro and reduced tumor burden and prolonged survival in an orthotopic G3MB mouse model. The current study illustrates how inducing iron overload by inhibiting mitochondrial Fe-S cluster transport can trigger ferroptosis and potentiate cisplatin action in G3MB cancer cells and tumors. Our study also provides evidence for using an FDA-approved drug with ferroptosis-inducing properties to potentiate classical chemotherapy in treating G3MB tumors.
Kanchan et al. (Fri,) studied this question.