Phase II study of atorvastatin in combination with radiotherapy and temozolomide in patients with glioblastoma.

Altwairgi, Abdullah; Alghareeb, Waleed; Alnajjar, Fouad; Mubasher, Mohammed; AlHussain, Hussain; Saleh, Rasha Mustafa

doi:10.1200/jco.2014.32.15_suppl.tps2102

Cited by 2 publications

(4 citation statements)

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“…As indicated above, the combination of other chemotherapy agents with statins may potentiate cell death induced by chemotherapy drugs alone. In support of this, a phase II clinical trial reported promising results using a combination of atorvastatin, TMZ, and radiotherapy . However, several studies have shown that despite the same impact on lipid profile, Simva exhibits less hepatotoxicity and gastrointestinal effects than atorvastatin .…”

Section: Discussionmentioning

confidence: 89%

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Simvastatin increases temozolomide‐induced cell death by targeting the fusion of autophagosomes and lysosomes

et al. 2019

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Temozolomide (TMZ) is a chemotherapy agent used to treat Grade IV astrocytoma, also known as glioblastoma (GBM). TMZ treatment causes DNA damage that results in tumor cell apoptosis and increases the survival rate of GBM patients. However, chemoresistance as a result of TMZ‐induced autophagy significantly reduces this anticancer effects over time. Statins are competitive inhibitors of HMG‐CoA reductase, the rate‐limiting enzyme of the mevalonate (MEV) cascade. Statins are best known for their cholesterol (CH)‐lowering effect. Long‐term consumption of statins, prior to and in parallel with other cancer therapeutic approaches, has been reported to increase the survival rate of patients with various forms of cancers. In this study, we investigated the potentiation of TMZ‐induced apoptosis by simvastatin (Simva) in human GBM cell lines and patient GBM cells, using cell monolayers and three‐dimensional cell culture systems. The incubation of cells with a combination of Simva and TMZ resulted in a significant increase in apoptotic cells compared to cells treated with TMZ alone. Incubation of cells with CH or MEV cascade intermediates failed to compensate the decrease in cell viability induced by the combined Simva and TMZ treatment. Simva treatment inhibited the autophagy flux induced by TMZ by blocking autophago‐lysosome formation. Our results suggest that Simva sensitizes GBM cells to TMZ‐induced cell death in a MEV cascade‐independent manner and identifies the inhibition of autophagosome‐lysosome fusion as a promising therapeutic strategy in the treatment of GBM.

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Section: Discussionmentioning

confidence: 89%

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confidence: 76%

Simvastatin increases temozolomide‐induced cell death by targeting the fusion of autophagosomes and lysosomes

et al. 2019

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“…Of note, a big cohort study conducted on patients with different types of cancers reported increased survival rate of patients with long-term consumption of statins,3 and another subsequent study in glioblastoma patients showed the same results 43. Thus, the cholesterol-lowering drugs, statins, may potentially serve as a new therapeutic approach for combination therapy in glioblastoma 44…”

Section: Cholesterol Metabolism In Cancermentioning

confidence: 89%

“…43 Thus, the cholesterol-lowering drugs, statins, may potentially serve as a new therapeutic approach for combination therapy in glioblastoma. 44 In summary, a deeper understanding of the role of cholesterol metabolism and transport in GBM cells and the underlying mechanisms of cholesterol-related drug resistance will be useful in improving current treatment strategies for patients with GBM. Mevalonate biology and autophagy are intimately linked at a more fundamental cellular level, where both pathways are amenable to pharmacologic manipulation.…”

Section: Cholesterol Metabolism In Cancermentioning

confidence: 99%

Targeting Cholesterol Metabolism in Glioblastoma: A New Therapeutic Approach in Cancer Therapy

Pirmoradi

Seyfizadeh

Ghavami³

et al. 2019

Journal of Investigative Medicine

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Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumor known with a poor survival rate despite current advances in the field of cancer. Additional research into the pathophysiology of GBM is urgently needed given the devastating nature of this disease. Recent studies have revealed the unique cellular physiology of GBM cells as compared with healthy astrocytes. Intriguingly, GBM cells are incapable of de novo cholesterol synthesis via the mevalonate pathway. Thus, the survival of GBM cells depends on cholesterol uptake via low-density lipoprotein receptors (LDLRs) in the form of apolipoprotein-E-containing lipoproteins and ATP-binding cassette transporter A1 (ABCA1) that efflux surplus cholesterol out of cells. Liver X receptors regulate intracellular cholesterol levels in neurons and healthy astrocytes through changes in the expression of LDLR and ABCA1 in response to cholesterol and its derivatives. In GBM cells, due to the dysregulation of this surveillance pathway, there is an accumulation of intracellular cholesterol. Furthermore, intracellular cholesterol regulates temozolomide-induced cell death in glioblastoma cells via accumulation and activation of death receptor 5 in plasma membrane lipid rafts. The mevalonate pathway and autophagy flux are also fundamentally related with implications for cell health and death. Thus, via cholesterol metabolism, the mevalonate pathway may be a crucial player in the pathogenesis and treatment of GBM where our current understanding is still lacking. Targeting cholesterol metabolism in GBM may hold promise as a novel adjunctive clinical therapy for this devastating cancer.

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Phase II study of atorvastatin in combination with radiotherapy and temozolomide in patients with glioblastoma.

Cited by 2 publications

References 0 publications

Simvastatin increases temozolomide‐induced cell death by targeting the fusion of autophagosomes and lysosomes

Simvastatin increases temozolomide‐induced cell death by targeting the fusion of autophagosomes and lysosomes

Targeting Cholesterol Metabolism in Glioblastoma: A New Therapeutic Approach in Cancer Therapy

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