Exth-24. Mgmt Inhibition by Disulfiram/copper Complex Restores Veliparib Enhancing Temozolomide Effect in Unfavorable Glioblastoma Multiforme
Year: 2017
Type: conference-abstract
Abstract: O6 methylguanine DNA methyltransferase (MGMT), a DNA repair enzyme, is over expressed in majority of glioblastoma multiforme (GBM) patients. MGMT overexpression causes temozolomide (TMZ) resistance. Poly (ADP – ribose) polymerase (PARP), another early DNA damage response system, like MGMT, has multiple other roles in maintaining genomic stability, coordinating cell cycle, apoptosis and inflammatory responses. Research and clinical evidence show that PARP inhibition in cancers harboring other DNA repair defects (most noticeable in BRCA mutated/defective cancers) limits cancer growth and enhances chemotherapy. Veliparib (ABT-888) is a potent PARP inhibitor. Disulfiram (DSF)/copper combination effectively inhibits MGMT and enhances Temozolomide effect in unfavorable (MGMT unmethylated) glioblastoma cell lines. Prior studies have suggested that Veliparib did not enhance Temozolomide activity in glioblastoma patients due to high MGMT expression levels. Here, we tested DSF/Cu combination in presence of Veliparib +/- Temozolomide in patient derived MGMT positive glioblastoma cell lines. Our results indicate that addition of Veliparib (to Temozolomide) did not significantly increase growth inhibition even at higher concentrations (up to 60µM) in both patient derived or established MGMT positive glioblastoma cells. Single agent treatment with DSF or copper, Temozolomide or Veliparib did not affect patient derived brain tumor cell growth. DSF/Cu complex significantly sensitized patient derived brain tumor cells to Veliparib alone (90%) and Veliparib + Temozolomide (95%) combination. In addition, Veliparib significantly increased apoptotic cell death when used in combination with DSF/Cu or DSF/Cu + Temozolomide. These treatment combinations also showed significant caspase 3/7 activation. Our findings suggest that MGMT inhibition via DSF/Cu complex restores Veliparib (Temozolomide enhancing) activity in patient derived glioblastoma cells.
Source: Neuro-Oncology
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2767411461