Targeting Glioblastoma Stem Cells to Overcome Chemoresistance: An Overview of Current Therapeutic Strategies

Abstract

Glioblastoma (GBM) is the most malignant primary brain tumor. The current standard approach in GBM is surgery, followed by treatment with radiation and temozolomide (TMZ); however, GBM is highly resistant to current therapies, and the standard of care has not been revised over the last two decades, indicating an unmet need for new therapies. GBM stem cells (GSCs) are a major cause of chemoresistance due to their ability to confer heterogeneity and tumorigenic capacity. To improve patient outcomes and survival, it is necessary to understand the properties and mechanisms underlying GSC chemoresistance. In this review, we describe the current knowledge on various resistance mechanisms of GBM to therapeutic agents, with a special focus on TMZ, and summarize the recent findings on the intrinsic and extrinsic mechanisms of chemoresistance in GSCs. We also discuss novel therapeutic strategies, including molecular targeting, autophagy inhibition, oncolytic viral therapy, drug repositioning, and targeting of GSC niches, to eliminate GSCs, from basic research findings to ongoing clinical trials. Although the development of effective therapies for GBM is still challenging, this review provides a better understanding of GSCs and offers future directions for successful GBM therapy.

TRPML2 Mucolipin Channels Drive the Response of Glioma Stem Cells to Temozolomide and Affect the Overall Survival in Glioblastoma Patients

“…Drug membrane transporters from ATP-binding cassette (ABC) sub-family A, B, C and D, solute carrier transporter (SLC) and aquaporin (AQP) families play a main role in the resistance of GBM stem cells to TMZ and other anti-neoplastic agents employed in the care of glioma tumors [ 24 ]. Thus, the expression of ABC, SLC and AQP drug transporter genes was evaluated in TRPML2-negative GSC#1 and TRPML2-positive GSC#83 lines by RT2 Profiler PCR Array ( Table S2 ).…”

DGKB mediates radioresistance by regulating DGAT1-dependent lipotoxicity in glioblastoma

“…Although TMZ is the only chemotherapeutic agent currently used in GBM patients, approximately half of treated patients do not respond to TMZ due to their tumors overexpressing O 6 -methylguanine-DNA methyltransferase (MGMT). 25 Moreover, most drugs developed for GBM treatment over the past 20 years failed in clinical trials due to various challenges, including inefficient drug delivery and severe side effects. In this regard, we investigated existing blood-brain barrier (BBB)-penetrating radiosensitizers with dual functions of activating DGKB and inhibiting DGAT1 by interrogating The Connectivity Map (CMap).…”

The effect of Azo-dyes on glioblastoma cells in vitro

“…It is well known that TMZ induces cell cycle arrest in G2/M, eventually leading to apoptosis ( Chien et al, 2021 ). At the moment, this alkylating agent has been widely used to treat GB, and many methods have been developed both to enhance its activity and to reduce the chemoresistance ( Akbarnejad et al, 2017 , Gerlach et al, 2022 , Kang et al, 2022 , Shao et al, 2019 ). Also, attention must be paid to concomitant administration of other medication, due to their influence on the TMZ efficacy ( Drljača et al, 2022 ).…”