Exth-54. Metformin Acts Synergistically With Gallium Maltolate to Inhibit the Proliferation of Glioblastoma Cells by Action on Mitochondrial Function
Year: 2017
Type: conference-abstract
Abstract: There is a vital need for new therapeutics to treat glioblastoma (GBM). Recently, we showed that gallium maltolate (GaM) inhibits the iron-dependent growth of GBM in vitro and in vivo. Here, we investigated whether metformin, an antidiabetic drug that can enter the brain, could potentiate the anti-GBM action of GaM. Adult D54 and U87-MG GBM cells were incubated with GaM and metformin, alone or in combination, for various times. Cell growth was measured by cytotoxicity assay. Drug synergy was calculated using Calcusyn computer program. Cellular mitochondrial function was measured using a Seahorse XFp Extracellular Flux Analyzer. Transferrin (Tf) receptor (TfR, iron uptake protein) and ferritin (Ftn, iron storage protein) levels were measured in GaM- and metformin–treated cells by 125I-Tf binding assay and Western blot. Metformin (0–2 mM) and GaM (0–100 µM)) individually inhibited the growth of U87 and D54 cells in a dose- and time-dependent manner. In combination, the drugs inhibited cell growth with a Combination Index (CI) of <1, consistent with drug synergy. At 24 h of incubation, prior to a decrease in proliferation, GaM and metformin individually suppressed cellular oxygen consumption rate (OCR) and their combination further blocked cellular OCR, consistent with synergistic inhibition of mitochondrial function. Cellular H-Ftn levels were decreased by metformin and increased by GaM. Metformin and GaM increased TfR expression 2 -3 fold whereas their combination increased TfR by only 1.2-fold above control cells. Metformin synergistically enhances GaM’s activity against glioblastoma. Both drugs perturb tumor iron homeostasis, which leads to changes in iron uptake and storage proteins. Metformin inhibits mitochondrial complex 1, whereas GaM inhibits Fe-dependent mitochondrial function and ribonucleotide reductase. Together, they synergistically inhibit mitochondrial function and block cell proliferation in GBM. Further studies will examine the potential of combination metformin and GaM in an animal model.
Source: Neuro-Oncology
Institution: Medical College of Wisconsin
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2767389620