Atorvastatin in combination with radiotherapy and temozolomide for glioblastoma: a prospective phase II study

Altwairgi, Abdullah; Alghareeb, Waleed; Alnajjar, Fouad; AlHussain, Hussain; Alsaeed, Eyad; Balbaid, Ali Abdullah O; Aldanan, S.; Orz, Yasser; Alsharm, Abdullah

doi:10.1007/s10637-020-00992-5

Cited by 32 publications

(33 citation statements)

References 14 publications

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“…However, brain tumors, especially the GBM derived from malignantly transformed astrocytes, create uneven permeability of the blood-brain barrier. The newly formed blood-brain tumor barrier has a certain permeability to lipoproteins and can also lead to an increase in brain cholesterol levels, which may be one of the reasons for the treatment resistance of patients with hyperlipidemia (Yan et al 2020;Altwairgi et al 2021). Thus, the brain tumor microenvironment has high levels of cholesterol that can be utilized by GBM cells.…”

Section: Discussionmentioning

confidence: 99%

“…The increase in cholesterol and LDL levels promoted resistance of multiple tumors to chemotherapy, and it is also an independent risk factor for poor prognosis of GBM under standard TMZ treatment. Statins improved the e cacy of TMZ and other cytotoxic agents by exhausting cholesterol (Yan et al 2020;Altwairgi et al 2021), revealing the potential correction of cholesterol and drug resistance. Although the mechanism of cholesterol-induced drug resistance has not been clari ed in CNS tumors, it has been proved that elevated cholesterol in malignant ascites induced chemotherapy resistance by upregulating the drug e ux proteins ABCG1 and MDR1 (Kim et al 2018).…”

Section: Introductionmentioning

confidence: 99%

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Cholesterol Analogs Ginsenosides Rg1 and Compound K Control Temozolomide Resistance in Glioblastoma Cells by Regulating Cholesterol Efflux and Lipid Raft Distribution

Qiu,

Zhang,

et al. 2022

Preprint

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Enriched cholesterol in brain is involved in the resistance of glioblastoma to temozolomide treatment. Cholesterol efflux and lipid raft redistribution contribute to improving resistance. Ginsenosides are structurally similar to cholesterol and can alter cholesterol metabolism and lipid raft distribution, whose subtypes Rb1, Rg1, Rg3 and Compound K showed brain permeability. From CGGA database, the expression of cholesterol efflux gene NR1H3 (LXRα) in tumor tissues of patients treated with temozolomide was positively correlated with long-term survival, and was negatively correlated with multidrug resistance protein (MDR)-1 located in lipid rafts. MDR1 level was correlated with cholesterol uptake (LDLR) and synthesis (SREBF2) genes, suggesting that cholesterol is involved in temozolomide resistance. We demonstrated that cholesterol protected the survival of resistant U251 cells from temozolomide stress, and upregulated MDR1. Resistant U251 cells tended to store cholesterol intracellularly, with weaker cholesterol efflux and LXRα expression to maintain a uniform distribution of lipid rafts. Ginsenosides Rb1, Rg1, Rg3 and Compound K reduced intracellular cholesterol content and promoted cholesterol efflux in resistant cells, making lipid raft distribution no longer uniform. Rg1 and Compound K also upregulated LXRα expression and induced the cytotoxicity of temozolomide in the presence of cholesterol. We further found that cholesterol efflux induction, lipid raft redistribution, and temozolomide sensitization by Rg1 and Compound K were induced through stimulation of LXRα. Therefore, ginsenoside Rg1 and Compound K can control temozolomide resistance in glioblastoma cells by regulating cholesterol metabolism, which are potential synergists for temozolomide therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cholesterol Analogs Ginsenosides Rg1 and Compound K Control Temozolomide Resistance in Glioblastoma Cells by Regulating Cholesterol Efflux and Lipid Raft Distribution

Qiu,

Zhang,

et al. 2022

Preprint

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“…However, RAB38 function can be inhibited using currently available pharmacological agents. Statins, which are FDA-approved and in wide clinical use, are known to inhibit RAB prenylation [ 34 ] and have been shown in a few previous studies to enhance temozolomide-induced glioblastoma cell death [ 35 , 36 , 37 ] and to induce a significant reduction in tumor volume in vivo [ 38 , 39 , 40 , 41 , 42 ]. Our studies demonstrated that treatment of glioblastoma cells with simvastatin or lovastatin causes a dose-dependent decrease in RAB38 expression and cell viability in LN229, T98G, and GBM43 cells in vitro ( Figure 6 , Supplementary Figure S2 ), which to the best of our knowledge has not been reported previously.…”

Section: Discussionmentioning

confidence: 99%

RAB38 Facilitates Energy Metabolism and Counteracts Cell Death in Glioblastoma Cells

Bianchetti

Bates

Nguyen

et al. 2021

Cells

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Glioblastoma is a high-grade glial neoplasm with a patient survival of 12–18 months. Therefore, the identification of novel therapeutic targets is an urgent need. RAB38 is a GTPase protein implicated in regulating cell proliferation and survival in tumors. The role of RAB38 in glioblastoma is relatively unexplored. Here, we test the hypothesis that RAB38 regulates glioblastoma growth using human glioblastoma cell lines. We found that genetic interference of RAB38 resulted in a decrease in glioblastoma growth through inhibition of proliferation and cell death induction. Transcriptome analysis showed that RAB38 silencing leads to changes in genes related to mitochondrial metabolism and intrinsic apoptosis (e.g., Bcl-xL). Consistently, rescue experiments demonstrated that loss of RAB38 causes a reduction in glioblastoma viability through downregulation of Bcl-xL. Moreover, RAB38 knockdown inhibited both glycolysis and oxidative phosphorylation. Interference with RAB38 enhanced cell death induced by BH3-mimetics. RAB38 antagonists are under development, but not yet clinically available. We found that FDA-approved statins caused a rapid reduction in RAB38 protein levels, increased cell death, and phenocopied some of the molecular changes elicited by loss of RAB38. In summary, our findings suggest that RAB38 is a potential therapeutic target for glioblastoma treatment.

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“…Like other statin medications, atorvastatin, a lipid-lowering drug, is also known to inhibit the HMG-CoA reductase, thereby control the endogenous production of cholesterol in the liver, and reduce the risk of cardiovascular disease. Further, combination of atorvastatin and aspirin is used for SARS-CoV-2 infection [55][56][57].…”

Section: Atorvastatin (12)mentioning

confidence: 99%

Therapeutic potential of pyrrole and pyrrolidine analogs: an update

Basha¹,

Basavarajaiah²,

Shyamsunder³

2022

Mol Divers

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The chemistry of nitrogen-containing heterocyclic compound pyrrole and pyrrolidine has been a versatile field of study for a long time for its diverse biological and medicinal importance . Biomolecules such as chlorophyll, hemoglobin, myoglobin, and cytochrome are naturally occurring metal complexes of pyrrole. These metal complexes play a vital role in a living system like photosynthesis, oxygen carrier, as well storage, and redox cycling reactions. Apart from this, many medicinal drugs are derived from either pyrrole, pyrrolidine, or by its fused analogs. This review mainly focuses on the therapeutic potential of pyrrole, pyrrolidine, and its fused analogs, more specifically anticancer, anti-inflammatory, antiviral, and antituberculosis. Further, this review summarizes more recent reports on the pyrrole, pyrrolidine analogs, and their biological potential. Graphical Abstract

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Atorvastatin in combination with radiotherapy and temozolomide for glioblastoma: a prospective phase II study

Cited by 32 publications

References 14 publications

Cholesterol Analogs Ginsenosides Rg1 and Compound K Control Temozolomide Resistance in Glioblastoma Cells by Regulating Cholesterol Efflux and Lipid Raft Distribution

Cholesterol Analogs Ginsenosides Rg1 and Compound K Control Temozolomide Resistance in Glioblastoma Cells by Regulating Cholesterol Efflux and Lipid Raft Distribution

RAB38 Facilitates Energy Metabolism and Counteracts Cell Death in Glioblastoma Cells

Therapeutic potential of pyrrole and pyrrolidine analogs: an update

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