DDDR-21. MPT0G521 AS A DUAL INHIBITOR OF LSD1 AND HDAC: A POTENTIAL THERAPEUTIC AGENT AGAINST PARENTAL AND TEMOZOLOMIDE-RESISTANT GLIOBLASTOMA MULTIFORME

Abstract INTRODUCTION Glioblastoma multiforme (GBM) is an aggressive brain tumor with limited treatment options and poor prognosis. Resistance to temozolomide (TMZ), the standard chemotherapy for GBM, further complicates treatment. This study investigates the effects of MPT0G521, a dual inhibitor of LSD1 and HDAC, on both parental and TMZ-resistant GBM cells to determine its potential as a therapeutic agent. MATERIALS AND METHODS TMZ and MPT0G521 were introduced in our study. Human GBM cell lines A172 and patient-derived primary GBM cells Pt#3, along with their TMZ-resistant counterparts, were cultured under specified conditions. Assays conducted include cell proliferation (MTT), colony formation, cell cycle analysis via flow cytometry, and western blot analysis for protein expression. Statistical significance was evaluated using ANOVA. RESULTS MPT0G521 exhibited significant anti-proliferative activity and toxicity against both parental and TMZ-resistant GBM cells in a dose- and time-dependent manner. Treatment with MPT0G521 led to reduced cell viability and colony formation. Cell cycle analysis revealed G2M phase arrest and increased subG1 phase, indicating cell cycle disruption and apoptosis. Western blot analysis showed upregulation of histone H3 methylation and acetylation, confirming the dual inhibitory action of MPT0G521 on LSD1 and HDAC. Additionally, MPT0G521 modulated markers of cell cycle and apoptosis, including increased levels of cleaved caspase-3 and PARP. CONCLUSION MPT0G521 demonstrates potential as an effective therapeutic agent against GBM by inhibiting cell proliferation, inducing cell cycle arrest, and promoting apoptosis in both parental and TMZ-resistant cells. These findings support further investigation of MPT0G521 as a promising treatment for GBM, particularly in cases resistant to standard chemotherapy.