temozolomide + valproic acid

A combination therapy consisting of temozolomide, an alkylating agent, and valproic acid, a histone deacetylase inhibitor. Temozolomide is a standard chemotherapeutic agent for glioblastoma that works by methylating DNA at various positions, leading to DNA damage and cell death. It's a prodrug that undergoes spontaneous conversion at physiological pH to its active form, which releases a highly reactive methyl diazonium cation capable of methylating DNA bases[5]. Valproic acid, while primarily known as an antiepileptic drug, functions as a histone deacetylase inhibitor (HDACi) in this context. This epigenetic modulation can sensitize glioblastoma cells to radiation and chemotherapy[1][8]. VPA appears to enhance the effectiveness of TMZ through several mechanisms: 1. Increasing TMZ uptake by tumor cells[6] 2. Potentially downregulating MGMT expression, which is involved in TMZ resistance[6][8] 3. Enhancing p53 activation and promoting expression of pro-apoptotic proteins like PUMA[8] 4. Inducing autophagy in glioma cells[7] 5. Causing cell-cycle arrest in G1 and/or G2 phase[6]