Gallium maltolate causes genomic instability to enhance glioblastoma response to radiation and temozolomide

Abstract Background Glioblastoma (GBM) represents the most common and aggressive central nervous system malignancy where overall survival is a dismal 14.6 months despite an aggressive standard of care treatment regimen that includes maximally safe surgical resection, radiotherapy, and temozolomide. It has recently been established that GBM tumors have increased transferrin receptor expression and iron content which corresponds with worse patient prognosis. This has led to the hypothesis that iron metabolism is a viable therapeutic target. An emergent therapeutic strategy to target GBM iron metabolism is gallium maltolate (GaM), which is an orally bioavailable form of Ga3+ that functions as a redox inactive iron mimic to disrupt iron metabolism. As mitochondrial iron metabolism serves as a central connection point between iron and DNA metabolism, the goal of this study was to determine if GaM could disrupt this system. Methods The effects of GaM on GBM cells were interrogated using conventional techniques including colony formation assays to assess clonogenicity, alkaline comet assays to evaluate DNA damage induction, and MitoFerro Green analysis to evaluate mitochondrial iron content. The effects of GaM on tumor growth in vivo were evaluated using a subcutaneous flank xenograft model system to determine the induction of DNA damage and an orthtopic model system to evaluate the combinatorial effects of GaM, radiation, and temozolomide on murine survival. Results This study uncovered that maintenance of high mitochondrial iron content corresponds with increased proliferative capacity in GBM cells. This study also shows that GaM can deplete mitochondrial iron to induce DNA damage both in vitro and in a subcutaneous xenograft model. Furthermore, GaM enhances the efficacy of radiation and temozolomide when delivered concomitant and adjuvantly in an orthotopic GBM model system. Conclusion These results suggest that GaM warrants further consideration for use in combination with standard of care GBM therapy.