Oncotarget

Research Papers:

The cytotoxicity of gallium maltolate in glioblastoma cells is enhanced by metformin through combined action on mitochondrial complex 1

Hisham S. Alhajala, John L. Markley, Jin Hae Kim, Mona M. Al-Gizawiy, Kathleen M. Schmainda, John S. Kuo and Christopher R. Chitambar _

PDF  |  Full Text  |  How to cite  |  Order a Reprint

Oncotarget. 2020; 11:1531-1544. https://doi.org/10.18632/oncotarget.27567

Metrics: PDF 703 views  |   Full Text 850 views  |   ?  


Abstract

Hisham S. Alhajala1, John L. Markley2, Jin Hae Kim2, Mona M. Al-Gizawiy3, Kathleen M. Schmainda3, John S. Kuo4 and Christopher R. Chitambar1,3

1 Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA

2 Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA

3 Department of Biophysics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA

4 Department of Neurosurgery and Mulva Clinic for the Neurosciences, Dell Medical School, Austin, Texas, USA

Correspondence to:

Christopher R. Chitambar,email: chitambr@mcw.edu

Keywords: glioblastoma; iron; gallium; metformin; mitochondrial complex I

Received: February 01, 2020     Accepted: April 03, 2020     Published: April 28, 2020

ABSTRACT

New drugs are needed for glioblastoma, an aggressive brain tumor with a dismal prognosis. We recently reported that gallium maltolate (GaM) retards the growth of glioblastoma in a rat orthotopic brain tumor model by inhibiting mitochondrial function and iron-dependent ribonucleotide reductase (RR). However, GaM’s mechanism of action at the mitochondrial level is not known. Given the interaction between gallium and iron metabolism, we hypothesized that gallium might target iron-sulfur (Fe-S) cluster-containing mitochondrial proteins. Using Extracellular Flux Analyzer technology, we confirmed that after a 24-h incubation, GaM 50 μmol/L inhibited glioblastoma cell growth by <10% but inhibited cellular oxygen consumption rate by 44% and abrogated mitochondrial reserve capacity. GaM blocked mitochondrial complex I activity and produced a 2.9-fold increase in cellular ROS. NMR spectroscopy revealed that gallium binds to IscU, the bacterial scaffold protein for Fe-S cluster assembly and stabilizes its folded state. Gallium inhibited the rate of in vitro cluster assembly catalyzed by bacterial cysteine desulfurase in a reaction mixture containing IscU, Fe (II), DTT, and L-cysteine. Metformin, a complex I inhibitor, enhanced GaM’s inhibition of complex I, further increased cellular ROS levels, and synergistically enhanced GaM’s cytotoxicity in glioblastoma cells in 2-D and 3-D cultures. Metformin did not affect GaM action on cellular iron uptake or transferrin receptor1 expression nor did it enhance the cytotoxicity of the RR inhibitor Didox. Our results show that GaM inhibits complex I by disrupting iron-sulfur cluster assembly and that its cytotoxicity can be synergistically enhanced by metformin through combined action on complex I.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 27567