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Boric acid Increases Susceptibility to Chemotherapy by Targeting the Ferritinophagy Signaling Pathway in TMZ Resistant Glioblastoma Cells

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Abstract

Glioblastoma (GBM) is a common and highly lethal form of brain cancer. Temozolomide (TMZ) is the primary chemotherapy used for GBM, but it has limited effectiveness, with about half of the patients developing resistance. Iron regulatory proteins (IRPs) modulate genes involved in iron metabolism, while the nuclear receptor coactivator 4 (NCOA4) controls iron metabolism through a process called ferritinophagy. In this study, we investigated whether boric acid increases chemosensitivity mediated by ferritinophagy via the NCOA4 and IRP2 signaling pathways in TMZ-resistant GBM cells. First, we generated TMZ-resistant GBM cells (A172-R and T98G-R cells). Next, we investigated the effects of boric acid on cell viability, proliferation, cell cycle, and cell morphology in these cells. Additionally, following boric acid treatment, we analyzed the expression and protein levels of various biochemical markers in these cells. Boric acid treatment in A172-R and T98G-R cells suppressed cell viability and proliferation, arrested these cells in the G1/G0 cell cycle, and induced morphological differences. Boric acid increased NCOA4, IRP2, iron, and malondialdehyde (MDA) levels in A172-R and T98G-R cells, while glutathione (GSH) and glutathione peroxidase 4 (GPx4) levels decreased. Moreover, boric acid treatment increased intracellular iron levels and lipid peroxidation by inducing NCOA4 and IRP2 expression levels in TMZ-resistant cells. According to our results, boric acid may regulate chemosensitivity in A172-R and T98G-R cells mediated by NCOA4 and IRP2. In conclusion, the manipulative effects of boric acid on the ferritinophagy pathway hold the potential to sensitize TMZ-resistant GBM cells to chemotherapy.

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Data Availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

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Authors and Affiliations

  1. Faculty of Pharmacy, Department of Biochemistry, Düzce University, Düzce, Turkey

    Ceyhan Hacioglu

  2. Faculty of Medicine, Department of Medical Biochemistry, Düzce University, Düzce, Turkey

    Ceyhan Hacioglu

  3. Faculty of Medicine, Department of Neurosurgery, Düzce University, Düzce, Turkey

    Cengiz Tuncer

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Ceyhan Hacioglu contributed to the study conception and design. Material preparation, data collection and analysis were performed by Ceyhan Hacioglu and Cengiz Tuncer. The first draft of the manuscript was written by Ceyhan Hacioglu. All authors read and approved the final manuscript.

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Correspondence to Ceyhan Hacioglu.

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Hacioglu, C., Tuncer, C. Boric acid Increases Susceptibility to Chemotherapy by Targeting the Ferritinophagy Signaling Pathway in TMZ Resistant Glioblastoma Cells. Biol Trace Elem Res (2023). https://doi.org/10.1007/s12011-023-03930-7

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