Cholesterol Derivatives as Promising Anticancer Agents in Glioblastoma Metabolic Therapy

Abstract

Malignant brain tumors are among the most devastating types of cancer. Glioblastoma is the most common and serious form of brain cancer. Most glioblastomas are surgically unresectable and are typically diagnosed at an advanced stage. The high level of resistance to chemotherapy, radiotherapy and immunotherapy makes glioblastoma one of the most difficult cancers to treat. In brain tumors, the challenges of targeted therapy also include the blood-brain barrier, which often contributes to treatment failure. Therefore, developments of new treatment strategies are required. Metabolic treatments could be an alternative to conventional therapies. Metabolic approaches aim at suppressing glioblastoma tumorigenicity leading to glioblastoma cell death. Since cholesterol metabolism is deregulated in these tumors, this is a promising potential target for therapy. As glioblastoma cells draw on cholesterol from the central nervous system to survive,

Ferroptosis sensitization in glioma: exploring the regulatory mechanism of SOAT1 and its therapeutic implications

“…The relationship between the MVA signaling pathway of cholesterol metabolism and ferroptosis is of great importance for understanding the molecular mechanisms of intracellular interactions and exploring therapeutic approaches that can interfere with both cholesterol metabolism and ferroptosis sensitivity. This provides the opportunity to regulate ferroptosis sensitivity while interfering with the cholesterol metabolic pathway, and the combined antitumor effects may have clinical application potential [49]. Cholesterol esterification is a mechanism by which the body stores and transfers cholesterol and avoids cellular toxicity caused by excess unesterified cholesterol.…”

A review of natural products and small‐molecule therapeutics acting on central nervous system malignancies: Approaches for drug development, targeting pathways, clinical trials, and challenges

“…β-Sitosterol has shown apoptosis in HAAE-2 (human abdominal aorta endothelial cells), inducing caspase-3 activity in the cells that corresponded the DNA fragmentation analysis in a terminal uridine deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) study (Rubis et al, 2008). On the other hand, since cholesterol metabolism is deregulated in these tumors, potentially toxic cholesterol analogues and phytosterol derivatives, and LXRs (Liver X Receptors) might be beneficial in metabolic treatments to suppress glioblastoma tumorigenicity, which can lead to glioblastoma cell death (Ahmad et al, 2019;Sassi et al, 2021). Phytosterol oxidative derivatives, known as oxyphytosterols, could also act as LXR activators (Blanco-Vaca et al, 2019).…”

Discovery and Optimization of N-Arylated Tetracyclic Dicarboximides That Target Primary Glioma Stem-like Cells

“…Using brain penetrant small molecule drugs to target metabolic anomalies in brain tumors is increasingly recognized as an appealing strategy, and cholesterol metabolism has been nominated as a GBM-specific vulnerability for GBM therapy hat can be exploited for therapy. − In contrast to peripheral organs, circulating lipoproteins do not provide cholesterol to the brain due to their inability to cross the blood-brain barrier. Therefore, CNS-resident cells, including GBM cells, are uniquely dependent on acquiring cholesterol from neighboring cells or synthesizing cholesterol de novo.…”

“…Activation of the EGFR/PI3K/Akt signaling pathway satisfies the increased demand for cholesterol of these rapidly dividing cells via the activation of LDLR-mediated uptake of exogenous cholesterol over SREBP-2 driven cholesterol biosynthesis (Figure A) . This rewiring of cholesterol homeostatic regulation in favor of uptake mechanisms is important for GBM cell fitness because oxysterols accumulate under conditions of high de novo cholesterol synthesis and activate liver X receptors (LXRs), ultimately causing cholesterol depletion. , Therefore, to reduce oxysterol accumulation, GBM cells display alterations in the expression of enzymes that oxidize cholesterol . Recognizing the importance of cholesterol to the growth of GBM cells, Mischel and co-workers investigated synthetic LXR agonists in preclinical models of GBM. , Ligand activated LXRs upregulate genes that reduce the cholesterol pool.…”

“…11 This rewiring of cholesterol homeostatic regulation in favor of uptake mechanisms is important for GBM cell fitness because oxysterols accumulate under conditions of high de novo cholesterol synthesis and activate liver X receptors (LXRs), ultimately causing cholesterol depletion. 9,12 Therefore, to reduce oxysterol accumulation, GBM cells display alterations in the expression of enzymes that oxidize cholesterol. 13 Recognizing the importance of cholesterol to the growth of GBM cells, Mischel and co-workers investigated synthetic LXR agonists in preclinical models of GBM.…”