Disulfiram Sensitizes a Therapeutic-Resistant Glioblastoma to the TGF-β Receptor Inhibitor

Abstract

Despite neurosurgery following radiation and chemotherapy, residual glioblastoma (GBM) cells develop therapeutic resistance (TR) leading to recurrence. The GBM heterogeneity confers TR. Therefore, an effective strategy must target cancer stem cells (CSCs) and other malignant cancer cells. TGF-β and mesenchymal transition are the indicators for poor prognoses. The activity of aldehyde dehydrogenases (ALDHs) is a functional CSC marker. However, the interplay between TGF-β and ALDHs remains unclear. We developed radiation-resistant and radiation-temozolomide-resistant GBM models to investigate the underlying mechanisms conferring TR. Galunisertib is a drug targeting TGF-β receptors. Disulfiram (DSF) is an anti-alcoholism drug which functions by inhibiting ALDHs. The anti-tumor effects of combining DSF and Galunisertib were evaluated by in vitro cell grow, wound healing, Transwell assays, and in vivo orthotopic GBM model. Mesenchymal-like phenotype was facilitated by TGF-β in TR GBM. Additionally, TR activated ALDHs. DSF inhibited TR-induced cell migration and tumor sphere formation. However, DSF did not affect the tumor growth in vivo. Spectacularly, DSF sensitized TR GBM to Galunisertib both in vitro and in vivo. ALDH activity positively correlated with TGF-β-induced mesenchymal properties in TR GBM. CSCs and mesenchymal-like GBM cells targeted together by combining DSF and Galunisertib may be a good therapeutic strategy for recurrent GBM patients.

Radiosensitizing effect of galunisertib, a TGF-ß receptor I inhibitor, on head and neck squamous cell carcinoma in vitro

“…The evident importance of the tumor microenvironment in TGF-ß signaling calls for more advanced cancer models, including cells of the tumor stroma, in future studies [38]. Notably, similar studies investigating the effect of Galunisertib both in vitro and in vivo, found consistent antineoplastic effects [33,39,40]. It can therefore reasonably be assumed that the observed effect of Galunisertib on HNSCC cell lines might also be relevant in vivo.…”

Molecular Pathways and Genomic Landscape of Glioblastoma Stem Cells: Opportunities for Targeted Therapy

“…The mechanism of action includes inhibition of HMG-CoA reductase by statins, resulting in downstream inhibition of Smad3 phosphorylation by Rho and ROCK [ 252 ]. Liu et al illustrated that the experimental compound galunisertib, which inhibits TGF-β receptor I kinase, can be deployed against GSCs in combination with the anti-alcohol drug disulfiram, which targets aldehyde dehydrogenases and sensitizes GSCs to the TGF-β receptor inhibitor [ 253 ]. Another inhibitor of the TGF-β receptor I, LY2109761, was shown to reduce expression of the CD44 stem cell marker in GSCs and reduce tumor growth and recurrence in an in vivo mouse model [ 254 ].…”

MDACT: A New Principle of Adjunctive Cancer Treatment Using Combinations of Multiple Repurposed Drugs, with an Example Regimen

“…C. Disulfiram in glioblastoma: With potential utility in treating glioblastoma with temozolomide, disulfiram irreversibly inactivates P-gp [171][172][173]. As with other cancers, the ALDH-positive glioblastoma subpopulation has other stem attributes, and is more chemotherapy resistant than the ALDH-negative subpopulation [158,[174][175][176]. D. Disulfiram in NSCLC: As it does in other cancers, ALDH contributes to driving stemness and, hence, cytotoxicity resistance, in NSCLC [177][178][179][180][181].…”