Role of glioblastoma stem cells in cancer therapeutic resistance: a perspective on antineoplastic agents from natural sources and chemical derivatives

Abstract

Glioblastoma (GBM) is the highest-grade form of glioma, as well as one of the most aggressive types of cancer, exhibiting rapid cellular growth and highly invasive behavior. Despite significant advances in diagnosis and therapy in recent decades, the outcomes for high-grade gliomas (WHO grades III-IV) remain unfavorable, with a median overall survival time of 15-18 months. The concept of cancer stem cells (CSCs) has emerged and provided new insight into GBM resistance and management. CSCs can self-renew and initiate tumor growth and are also responsible for tumor cell heterogeneity and the induction of systemic immunosuppression. The idea that GBM resistance could be dependent on innate differences in the sensitivity of clonogenic glial stem cells (GSCs) to chemotherapeutic drugs/radiation prompted the scientific community to rethink the understanding of GBM growth and therapies directed at eliminating these cells or modulating their stemness. This review aims to describe major intrinsic and extrinsic mechanisms that mediate chemoradioresistant GSCs and therapies based on antineoplastic agents from natural sources, derivatives, and synthetics used alone or in synergistic combination with conventional treatment. We will also address ongoing clinical trials focused on these promising targets. Although the development of effective therapy for GBM remains a major challenge in molecular oncology, GSC knowledge can offer new directions for a promising future.

Keywords: Chemoradioresistance; Clinical trials; Glial stem cell; Initiating cells; Natural products; Therapeutic strategies.

Fig. 1

Gliomas classification regarding the mutation status of isocitrate dehydrogenase 1 (IDH-1) gene. See text for details (created with Biorender.com)

Fig. 2

Schematic overview of the cellular components of the microenvironment of glioblastoma (GBM). GSC: glial stem cell; Tumor microenvironment is a complex network composed of stromal cells (fibroblasts, microglia, astrocyte), mesenchymal cells, stem cells, and immune and inflammatory cells (macrophages). The main biomarkers of glial stem cells are indicated (created with Biorender.com)

Fig. 3

A schematic representation of the molecular signaling hallmarks of glial stem cell (CSC) and the effect of natural compounds and synthetic drugs on these molecular targets. In the dark red circle are represented natural compounds that target each hallmark. In light red are represented chemicals/synthetic drugs that targeted each hallmark in GSC. See text for details (created with Biorender.com)