6-Gingerol overcomes TMZ resistance in GBM by suppressing EMT and cell migration via the PI3K/Akt/β-catenin/c-Myc pathway

May 29, 2025International immunopharmacology

6-Gingerol may overcome chemotherapy resistance in brain cancer by blocking cell movement and change through a key growth pathway

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Abstract

Treatment with 6-gingerol significantly reduced cell viability and migratory ability in TMZ-resistant glioblastoma cells.

TMZ-resistant glioblastoma cell lines showed increased migratory capacity and features of epithelial-mesenchymal transition (EMT).
Co-treatment with TMZ and 6-gingerol restored sensitivity to TMZ and increased cytotoxic effects in resistant cells.
6-Gingerol suppressed the activity of certain enzymes associated with tumor invasion and reversed EMT characteristics.
Activation of specific cellular signaling pathways was observed in TMZ-resistant cells, which may influence tumor growth and response to treatment.
In vivo studies indicated that 6-gingerol significantly inhibited tumor growth in a model of TMZ-resistant glioblastoma without causing toxicity.

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Glioblastoma multiforme (GBM) is the most aggressive and treatment-resistant primary brain tumor with acquired resistance to temozolomide (TMZ) posing a major clinical challenge. This study investigates the therapeutic potential of 6-gingerol, a bioactive compound from ginger, in overcoming TMZ resistance in GBM and delineates its molecular mechanisms. TMZ-resistant GBM cell lines (U87-TR and A172-TR) were established which exhibited enhanced migratory capacity and pronounced epithelial-mesenchymal transition (EMT) features. Treatment with 6-gingerol significantly reduced cell viability, colony formation, and migratory ability, as demonstrated by wound healing and transwell assays. Co-treatment with TMZ and 6-gingerol restored TMZ sensitivity and enhanced cytotoxicity in resistant cells. Mechanistically, 6-gingerol suppressed matrix metalloproteinases (MMP-2 and MMP-9) and reversed EMT, as indicated by the upregulation of epithelial markers and downregulation of mesenchymal markers. Western blot and transcriptomic analyses revealed activation of the PI3K/Akt/GSK-3β pathway and overexpression of β-catenin and c-Myc in TMZ-resistant cells. 6-Gingerol inhibited PI3K/Akt phosphorylation and downstream targets, notably reducing c-Myc levels. Pharmacological intervention confirmed that PI3K/Akt signaling governs c-Myc expression and EMT progression in TMZ-resistant GBM. In vivo, 6-gingerol markedly suppressed tumor growth in a TMZ-resistant xenograft model without observable toxicity, accompanied by inhibition of the PI3K/Akt/β-catenin/c-Myc axis. These findings demonstrate that 6-gingerol effectively reverses TMZ resistance and EMT-driven invasiveness, supporting its potential as a novel adjuvant strategy in GBM therapy.

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6-Gingerol overcomes TMZ resistance in GBM by suppressing EMT and cell migration via the PI3K/Akt/β-catenin/c-Myc pathway

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