Cholesteryl Esters of the Glioblastoma*

White, Harold B.; Smith, Robert R.

doi:10.1111/j.1471-4159.1968.tb11613.x

Cited by 11 publications

(4 citation statements)

References 27 publications

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“…This effect was statistically significantly amplified when quetiapine and radiation were combined and led to an upregulation of the intracellular levels of fatty acids and cholesterol esters species. Additionally, although the normal brain contains cholesterol, only its free form, sterol esters, has long been known to be specific for glioblastomas (38). In agreement with the literature, inhibition of the cholesterol biosynthesis using atorvastatin by itself had some effect on the self-renewal capacity of glioma-initiating cells in vitro, and this was enhanced by the addition of quetiapine but failed to radiosensitize glioma-initiating cells.…”

Section: Discussionsupporting

confidence: 80%

Dopamine Receptor Antagonists, Radiation, and Cholesterol Biosynthesis in Mouse Models of Glioblastoma

Bhat

Saki

Cheng

et al. 2021

JNCI: Journal of the National Cancer Institute

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Background Glioblastoma is the deadliest brain tumor in adults and the standard-of-care consists of surgery followed by radiation and treatment with temozolomide. Overall survival times for patients suffering from glioblastoma are unacceptably low indicating an unmet need for novel treatment options. Methods Using patient-derived HK-157, HK-308, HK-374, and HK-382 glioblastoma lines, the GL261 orthotopic mouse models of glioblastoma and HK-374 patient-derived orthotopic xenografts we tested the effect of radiation and the dopamine receptor antagonist quetiapine on glioblastoma self-renewal in vitro and survival in vivo. A possible resistance mechanism was investigated using RNA-Sequencing. The blood-brain-barrier-penetrating statin atorvastatin was used to overcome this resistance mechanism. All statistical tests were 2-sided. Results Treatment of glioma cells with the dopamine receptor antagonist quetiapine reduced glioma cell self-renewal in vitro and combined treatment of mice with quetiapine and radiation prolonged the survival of glioma-bearing mice. The combined treatment induced the expression of genes involved in cholesterol biosynthesis. This rendered GL261 and HK-374 orthotopic tumors vulnerable to simultaneous treatment with atorvastatin and further statistically significantly prolonged the survival of C57BL/6 (n = 10 to 16 mice per group; median survival not reached; Log-Rank test, p < 0.001) and NSG mice (n = 8 to 21 mice per group; hazard ratio = 3.96, 95% confidence interval = 0.29 to 12.40; Log-Rank test, p < 0.001), respectively. Conclusions Our results indicate promising therapeutic efficacy with the triple combination of quetiapine, atorvastatin and radiation treatment against glioblastoma without increasing the toxicity of radiation. With both drugs readily available for clinical use our study could be rapidly translated into a clinical trial.

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Section: Discussionsupporting

confidence: 80%

Dopamine Receptor Antagonists, Radiation, and Cholesterol Biosynthesis in Mouse Models of Glioblastoma

Bhat

Saki

Cheng

et al. 2021

JNCI: Journal of the National Cancer Institute

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“…The concentration of cholesterol esters is increased in brain tumours (WHITE and SMITH, 1968) and in certain demyelinating disorders (CUMMINGS, 1955). Since cholesterol esters occur in large amounts during the degradation of nervous tissue, ROSSITER (1 961) proposed the hypothesis that the accumulation of esterified cholesterol results from the degradation of the fatty acid-containing myelin lipids.…”

Section: Discussionmentioning

confidence: 99%

CHOLESTEROL ESTERS AND HYDROLYTIC CHOLESTEROL ESTERASE DURING WALLERIAN DEGENERATION¹

Mezei

1970

Journal of Neurochemistry

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To study the involvement of cholesterol esters in myelination and demyelination, we determined the concentration of free cholesterol and cholesterol esters and the activity of hydrolytic cholesterol esterase (sterol ester hydrolase; EC 3.1.1.13) in hen sciatic nerve during Wallerian degeneration. A progressive increase in the ratio of cholesterol ester to free cholesterol was observed in the degenerating nerve at 8, 16 and 32 days after nerve section. Hydrolytic cholesterol esterase activity decreased progressively in the degenerating nerves at the same time. 1163 1164 CATHER~NE MEZEI MATERIALS A N D METHODS Chemicals.All chemicals used were of analytical quality. Bio-Sil BH, 100-200 mesh (Bio-Rad Laboratories, Richmond, Calif.) was used for the column chromatographic separation of cholesterol esters from free cholesterol. Cholesteryl-7 a-['H$almitate (7.8 mCi/mg) was obtained from New England Nuclear COT. (Boston, Mass.) and purified by column chromotography (CREECH and SEWELL, 1962) prior to use. The radioactive substrate was stored at -15°C in acetone solution (4 x loK counts/min; 0.05 pg of cholesteryl palmitatel5 PI).Surgical technique. White Leghorn hens approx. 1 yr old and weighing 1-1.5 kg were used. The left sciatic nerve of each animal was cut at the level of the greater trochanter of the femur. A 2-3 mm piece was cut out from the proximal stump, and the end of the distal nerve was sutured to the overlying muscle to minimize the possibility of regeneration. The operation was performed under aseptic conditions. The animals were killed by decapitation at 8, 16 and 32 days and the segment of nerve distal to the site of operation was removed. At the same time, a closely similar length of the right sciatic nerve was removed to serve as a control. Both sciatic nerves were stripped of epineurium and adherent fat, and rapidly weighed. Nerves for chemical analyses were dropped immediately into liquid N2.Extraction and chemical anahsis offissues. Prior to extraction, the nerve samples were cut into small pieces. Five ml of methanol were added and the nerve was homogenized in a conical glass homogenizer. The homogenate was transferred into a 13-ml glass-stoppered centrifuge tube, shaken with a Vortex mixer and placed in an ice-bath for 10 min. It was then centrifuged at 4°C for 10 min at 340 g ; the supernatant solution was placed into glass-stoppered centrifuge tubes and 10 ml of chloroform were added. The precipitate was extracted, at room temperature, thrice with 10 ml of chloroform-methanol (2:l vlv) for 1 h, followed by centrifugation as above. These three lipid extracts were combined with the original one and washed twice according to the method of FOLCH-PI, LEES and SLOANE-STANLEY (1957), using first chicken-Ringer (0.12 M-NaC1; 0-002 M-CaCI, and 0.006 M-KC~) and then a mixture of chicken-Ringer and methanol (1 : 1 v/v). The combined lipid extracts were evaporated in uacuo at room temperature and placed in a desiccator over KOH overnight at 0°C. The residues were extracted several times with small portion...

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“…Not only can neoplastic cells increase exogenous lipid uptake and lipogenesis, but they have also shown an increased ability to store lipid and cholesterol esters inside the specialized intracellular vacuoles of LDs [ 47 ]. Prior to the genesis of lipidomics, cholesterol esters had already been established as a specific element of glioblastoma [ 48 ]. This is due to the established understanding that brain cholesterol is largely synthesized de novo, as peripheral cholesterol cannot readily cross the blood–brain barrier [ 49 ].…”

Section: Lipid Metabolism In Glioblastomamentioning

confidence: 99%

The Lipidomic Signature of Glioblastoma: A Promising Frontier in Cancer Research

Yu,

Aboud

2024

Cancers

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Glioblastoma is the most aggressive primary brain malignancy in adults, and has a survival duration of approximately 15 months. First line treatment involves surgical resection, chemotherapy, and radiation, but despite the multi-pronged approach and advances in cancer research, glioblastoma remains devastating with a high mortality rate. Lipidomics is an emerging discipline that studies lipid pathways and characteristics, and is a promising field to understand biochemical mechanisms. In glioblastoma, disrupted lipid homeostasis has been reported in the literature. A thorough understanding of serum lipidomics may offer ways to better understand glioblastoma biomarkers, prognosis, and treatment options. Here, we review the literature, offering future directions for lipidomics research in glioblastomas.

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Cholesteryl Esters of the Glioblastoma*

Cited by 11 publications

References 27 publications

Dopamine Receptor Antagonists, Radiation, and Cholesterol Biosynthesis in Mouse Models of Glioblastoma

Dopamine Receptor Antagonists, Radiation, and Cholesterol Biosynthesis in Mouse Models of Glioblastoma

CHOLESTEROL ESTERS AND HYDROLYTIC CHOLESTEROL ESTERASE DURING WALLERIAN DEGENERATION¹

The Lipidomic Signature of Glioblastoma: A Promising Frontier in Cancer Research

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Cholesteryl Esters of the Glioblastoma*

Cited by 11 publications

References 27 publications

Dopamine Receptor Antagonists, Radiation, and Cholesterol Biosynthesis in Mouse Models of Glioblastoma

Dopamine Receptor Antagonists, Radiation, and Cholesterol Biosynthesis in Mouse Models of Glioblastoma

CHOLESTEROL ESTERS AND HYDROLYTIC CHOLESTEROL ESTERASE DURING WALLERIAN DEGENERATION1

The Lipidomic Signature of Glioblastoma: A Promising Frontier in Cancer Research

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CHOLESTEROL ESTERS AND HYDROLYTIC CHOLESTEROL ESTERASE DURING WALLERIAN DEGENERATION¹