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

Chan-Chuan Liu,Chun-I Sze,Po-Wu Gean,Cheng-Lin Wu,Meng-Xuan Lin

doi:10.3390/ijms221910496

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.

Highlights

Glioblastoma (GBM) is the most malignant primary brain tumor in adults
aldehyde dehydrogenases (ALDHs) activity positively correlated with TGF-β-induced mesenchymal properties in therapeutic resistance (TR) GBM
The standard of care (SoC) of GBM consists of neurosurgical removal followed by radiotherapy, chemotherapy, radiochemotherapy, or a tumor treating field device, such as co-adjuvant therapy [1]

Summary

Introduction

Glioblastoma (GBM) is the most malignant primary brain tumor in adults. The standard of care (SoC) of GBM consists of neurosurgical removal followed by radiotherapy, chemotherapy, radiochemotherapy, or a tumor treating field device, such as co-adjuvant therapy [1]. Temozolomide (TMZ) is the most common drug used in GBM chemotherapy. Radiation is a powerful approach to controlling tumor growth and significantly improves patient survival [2]. The benefit of radiochemotherapy varies in the case of GBM [3]. According to the World Health Organization classification of tumors in the central nervous system, in spite of receiving SoC, the median time to recurrence is about

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