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Exploring the Therapeutic Potential of Dapagliflozin and Trigonelline in Sensitizing Temozolomide-Resistant Glioblastoma Multiforme Cells: Molecular Mechanisms and Therapeutic Implications
Other Title
Exploring the Therapeutic Potential of Dapagliflozin and Trigonelline in Sensitizing Temozolomide-Resistant Glioblastoma Multiforme Cells: Molecular Mechanisms and Therapeutic Implications
Type
thesis
Date Issued
2025-06-11
Author(s)
Sujatha Venkadagopal, Ridha Haritha
Advisor
黃旭山
Subjects
系所名稱：癌症生物學與藥物研發研究所碩士班
Publisher
癌症生物學與藥物研發研究所碩士班
Description
學位別：碩士
口試委員：黃旭山; 吳駿翃; 蔡淵欽
關鍵字：Glioblastoma、Combination Therapy、Tumoroids、GBM、signaling pathway、Dapagliflozin、Trigonelline、TMZ、repurposed drugs
口試委員：黃旭山; 吳駿翃; 蔡淵欽
關鍵字：Glioblastoma、Combination Therapy、Tumoroids、GBM、signaling pathway、Dapagliflozin、Trigonelline、TMZ、repurposed drugs
Abstract
Glioblastoma (GBM) remains one of the most aggressive and treatment-resistant brain malignancies, necessitating novel therapeutic strategies to enhance efficacy and overcome drug resistance. This study investigates the impact of Dapagliflozin (DAPA) and Trigonelline (TGN) monotherapy and their sequential combination with Temozolomide (TMZ) on GBM cell viability, molecular pathways, and immune modulation using 3D tumoroid models derived from U87MG, Glioma primary, and P-1 primary cells.
Cell viability assays revealed that the DAPA+TMZ combination exhibited superior or comparable cytotoxic effects relative to TGN+TMZ across different GBM cell lines, suggesting enhanced tumor sensitization. Microscopic analysis demonstrated that sequential treatment significantly reduced tumoroid mass and integrity, particularly in the presence of THP-1 cells, which contribute to GBM tumor resilience. qPCR analysis further confirmed the molecular impact of DAPA+TMZ treatment, revealing suppression of PI3K, AKT, and YAP-1 expression, alongside reductions in tumor evasion, mesenchymal, and glioma stem cell markers are the key regulators of GBM progression and recurrence. Crucially, macrophage polarization analysis indicated a favorable immunomodulatory shift, with increased expression of M1 pro-inflammatory markers and diminished expression of M2 tumor-supportive markers, fostering an immune microenvironment less conducive to GBM survival.
These findings collectively highlight the therapeutic potential of sequential DAPA+TMZ administration in overcoming TMZ resistance through direct cytotoxic effects, oncogenic pathway modulation, and immune microenvironment reprogramming. This study underscores the importance of integrating metabolic modulators into GBM treatment paradigms to enhance therapeutic efficacy and improve patient outcomes
Cell viability assays revealed that the DAPA+TMZ combination exhibited superior or comparable cytotoxic effects relative to TGN+TMZ across different GBM cell lines, suggesting enhanced tumor sensitization. Microscopic analysis demonstrated that sequential treatment significantly reduced tumoroid mass and integrity, particularly in the presence of THP-1 cells, which contribute to GBM tumor resilience. qPCR analysis further confirmed the molecular impact of DAPA+TMZ treatment, revealing suppression of PI3K, AKT, and YAP-1 expression, alongside reductions in tumor evasion, mesenchymal, and glioma stem cell markers are the key regulators of GBM progression and recurrence. Crucially, macrophage polarization analysis indicated a favorable immunomodulatory shift, with increased expression of M1 pro-inflammatory markers and diminished expression of M2 tumor-supportive markers, fostering an immune microenvironment less conducive to GBM survival.
These findings collectively highlight the therapeutic potential of sequential DAPA+TMZ administration in overcoming TMZ resistance through direct cytotoxic effects, oncogenic pathway modulation, and immune microenvironment reprogramming. This study underscores the importance of integrating metabolic modulators into GBM treatment paradigms to enhance therapeutic efficacy and improve patient outcomes