Anti-glioblastoma effects of dorzolamide alone and in combination with temozolomide on U87 cells and CD133+glioblastoma stem cells

Document Type

Article

Department

Pathology and Laboratory Medicine

Abstract

Introduction: Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with a poor prognosis, primarily due to therapy resistance mediated by CD133+ glioblastoma stem cells (GSCs). The BCL3 gene contributes to this resistance and is potentially regulated by Carbonic Anhydrase II (CA II). Additionally, BCL3 enhances β-catenin-mediated transcription, promoting tumor growth. Since CA II may modulate both BCL3 expression and Wnt/β-catenin signaling, its inhibition represents a promising therapeutic strategy. Therefore, this study investigated the antiglioblastoma potential of the CA II inhibitor Dorzolamide, alone and in combination with Temozolomide (TMZ), in U87 cells and CD133+ GSCs.
Methods: U87 cells were treated with Dorzolamide, TMZ, or both. MTT, migration, invasion, TUNEL, and cell cycle assays assessed proliferation, motility, apoptosis, and cell cycle arrest. CD133+ GSCs were isolated by MACS and characterized by flow cytometry. Neurosphere assays and RT-qPCR analyzed neurosphere formation and mRNA expression of CA II, BCL3, β- catenin, and Twist, respectively. β-catenin protein expression was evaluated by immunocytochemistry.
Results: Dorzolamide and TMZ significantly inhibited proliferation, migration, and invasion while promoting apoptosis in U87 cells; the combination had the strongest effect (P< 0.001). Cell cycle arrest occurred in G0/G1. Neurosphere formation by CD133+ GSCs was markedly reduced (P< 0.001). Expression of CA II, BCL3, β-catenin, and Twist was significantly downregulated in all treatment groups (P< 0.001).
Discussion: This study highlights FDA-approved CA II inhibitor Dorzolamide as a promising adjunct to TMZ therapy, effectively targeting GBM cells and therapy-resistant CD133+ GSCs. Its ability to inhibit CAII, BCL3, β-catenin, and Twist indicates its disruption of critical survival pathways in GSCs. However, further in vivo studies are required to confirm its therapeutic potential against GBM.

Conclusion: Dorzolamide inhibits GSC proliferation, promotes apoptosis in U87 cells, affects the cell cycle, and enhances TMZ activity, suggesting potential in GBM treatment.

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Publication (Name of Journal)

Current Molecular Medicine

DOI

10.2174/0115665240391781250731145446

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