A novel HPβCD-Cu(DDC)(2) delivery system in patient derived orthotopic xenograft targeting MGMT-mediated temozolomide resistance in glioblastoma

Document Type

Article

Publication Date

9-25-2025

Publication Title

Sci Rep

Abstract

The uniform lethality of glioblastoma (GBM) with a survival of less than 2 years despite best available therapy is attributed to treatment resistance due to DNA repair mechanisms that drive disease relapse and tumor heterogeneity. One prognostic factor identified as a reliable biomarker for GBM sensitivity to temozolomide (TMZ) and radiotherapy (RT) is the overexpression of O(6)-methylguanine-methyl-transferase (MGMT) enzyme. Patients with active MGMT were found to receive little benefit from TMZ and RT. They represent a group of great unmet need with no treatment options that significantly improve survival. Recently, several preclinical and clinical studies suggest that the alcohol aversion drug, disulfiram (DSF), inhibited MGMT and improved the efficacy of TMZ in GBM when combined with copper (Cu). However, phase II trial showed that there was no significant survival benefit from oral Cu/DSF. Nevertheless, the major limitation of oral Cu/DSF has been delivery of fragile DSF to the in vivo system. To address this limitation, we developed a novel delivery system using 2-hydroxypropyl beta cyclodextrin (HPβCD) encapsulating the Cu complex of DSF's active metabolite, diethyldithiocarbamic acid (DDC). It was determined that HPβCD stabilized Cu(DDC)(2). In vitro cell culture study revealed that HPβCD-Cu(DDC)(2) inhibited MGMT through the ubiquitin-proteasome pathway. Inhibition of MGMT activity in cell cultures vastly increased the alkylation-induced DNA double-strand breaks, cytotoxicity, and the levels of apoptotic markers like histone family member X (γ-H2AX), JNK-P and cleavage of Poly [ADP-ribose] polymerase 1 (PARP-1). Preliminary intravenous delivery of HPβCD-Cu(DDC)(2) in combination with TMZ in an MGMT-positive patient derived orthotopic xenograft (PDOX) model demonstrated tumor size regression. HPβCD-Cu(DDC)(2) targets MGMT-145-cysteine and its unique cytotoxic mechanism circumvents MGMT-mediated TMZ resistance. This novel delivery system shows promise for overcoming MGMT-mediated resistance in GBM, offering a potential new therapeutic strategy.

Medical Subject Headings

Glioblastoma; Temozolomide; Humans; Drug Resistance, Neoplasm; Animals; DNA Repair Enzymes; DNA Modification Methylases; Tumor Suppressor Proteins; Xenograft Model Antitumor Assays; Copper; Mice; Cell Line, Tumor; Disulfiram; Brain Neoplasms; Drug Delivery Systems; Antineoplastic Agents, Alkylating

PubMed ID

40998915

Volume

15

Issue

1

First Page

32869

Last Page

32869

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