BISDEMETHOXYCURCUMIN MODULATES MGMT ASSOCIATED CHEMORESISTANCE IN GLIOBLASTOMA CELL LINES WHILE EXHIBITING MINIMAL TOXICITY TO PRIMARY ASTROCYTES

Glioblastoma multiforme, a grade four astrocytoma, is the most aggressive primary brain tumor and is marked by poor clinical outcomes. Current treatments involving Temozolomide (TMZ), however, develop resistance. A major contributor to Temozolomide resistance is the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT), which removes the methyl group added by TMZ, thereby counteracting TMZ-induced DNA damage and limiting its therapeutic efficacy. In this study, we evaluated the anti-glioma efficacy of Bisdemethoxycurcumin (BDMC), a bioactive curcuminoid derived from Curcuma longa, to reverse MGMT-associated TMZ resistance in glioblastoma cells. We have isolated BDMC using silica gel column chromatography with chloroform: methanol as the mobile phase, increasing the polarity. Human glioblastoma cell lines LN229 and T98G were treated with BDMC alone and in combination with TMZ. Cell viability, ROS, and apoptosis were analysed using flow cytometry assays. To assess neurotoxicity, primary astrocytes isolated from mouse pup brains were treated with BDMC. BDMC significantly reduced GBM cell viability in a dose-dependent manner and promoted apoptotic cell death. BDMC enhanced TMZ-induced cytotoxicity by downregulating MGMT expression and potentiated the intrinsic apoptotic pathway, as evidenced by increased caspase-9 activity. Importantly, BDMC exhibited minimal cytotoxicity in primary astrocytes at concentrations effective against glioblastoma cells. Collectively, these findings demonstrate that BDMC can effectively sensitize the glioblastoma cells to TMZ resistance by targeting the MGMT mediated resistance mechanism while sparing the primary astrocytes. This study highlights that BDMC can be a promising therapeutic candidate for overcoming chemoresistance in glioblastoma and further supports its clinical evaluation in neurooncological therapy.