Acyl-coenzyme A: Cholesterol acyltransferase inhibitor Avasimibe affect survival and proliferation of glioma tumor cell lines

Bemlih, Sana; Poirier, Marie-Denise; Andaloussi, Abdeljabar El

doi:10.4161/cbt.9.12.11875

Cited by 78 publications

(73 citation statements)

References 15 publications

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“…We moreover demonstrated that cholesterol esterification in smooth muscle cells is a key event in vascular proliferative diseases [20]. Furthermore, inhibition of CEs synthesis partially blocked cell proliferation, although the extent of the latter effect was dependent on the cell type [20][21][22][23], suggesting the potential involvement of cholesterol esterification as a new pathway implicated in cell growth. On the other hand, several studies have demonstrated how proliferation of tumour cells is arrested in a delipidated medium, with inhibition being almost completely prevented following addition of LDL and/or HDL [24,25].…”

Section: Introductionmentioning

confidence: 81%

A lipoprotein source of cholesteryl esters is essential for proliferation of CEM-CCRF lymphoblastic cell line

et al. 2011

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Tumour are characterised by a high content of cholesteryl esters (CEs) stored in lipid droplets purported to be due to a high rate of intracellular esterification of cholesterol. To verify whether and which pathways involved in CE accumulation are essential in tumour proliferation, the effect of CE deprivation, from both exogenous and endogenous sources, on CEM-CCRF cells was investigated. Cholesterol synthesis, esterification and content, low-density lipoprotein (LDL) binding and high-density lipoprotein (HDL)-CE uptake were evaluated in cultured in both conventional and delipidated bovine serum with or without oleic or linoleic acids, cholesteryl oleate, LDL and HDL. High content of CEs in lipid droplets in this cell line was due to esterification of both newly synthesised cholesterol and that obtained from hydrolysis of LDL; moreover, a significant amount of CE was derived from HDL-CE uptake. Cell proliferation was slightly affected by either acute or chronic treatment up to 400 μM with Sz-58035, an acyl-cholesteryl cholesterol esterification inhibitor (ACAT); although when the enzyme activity was continuously inhibited, CE content in lipid droplets was significantly higher than those in control cells. In these cells, analysis of intracellular and medium CEs revealed a profile reflecting the characteristics of bovine serum, suggesting a plasma origin of CE molecules. Cell proliferation arrest in delipidated medium was almost completely prevented in the first 72 h by LDL or HDL, although in subsequent cultures with LDL, it manifested an increasing mortality rate. This study suggests that high content of CEs in CEM-CCRF is mainly derived from plasma lipoproteins and that part of CEs stored in lipid droplets are obtained after being taken up from HDL. This route appears to be up-regulated according to cell requirements and involved in low levels of c-HDL during cancer. Moreover, the dependence of tumour cells on a source of lipoprotein provides a novel impetus in developing therapeutic strategies for use in the treatment of some tumours.

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Section: Introductionmentioning

confidence: 81%

A lipoprotein source of cholesteryl esters is essential for proliferation of CEM-CCRF lymphoblastic cell line

et al. 2011

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“…The authors also proposed that Avasimibe could directly alter scavenger receptor (SR) function or number. Additionally, Bemlih and co-workers [11] suggested that Avasimibe could reduce ACAT-1 expression and cholesterol ester synthesis in glioma cell lines. In this work, we did not explore the potential mechanisms involved in the esterification of sterols in T .…”

Section: Resultsmentioning

confidence: 99%

“…Lipids were extracted using the Folch method as follows [11]: 12 mL of extraction solution (chloroform-methanol, 2:1, vol/vol) was added to a glass test tube containing 2 mL of sample to yield a final ratio of chloroform/methanol/water (4:2:1). The mixture was stirred vigorously using a vortex machine, and the suspension was kept at 5°C for five days.…”

Section: Methodsmentioning

confidence: 99%

Trypanosoma cruzi Epimastigotes Are Able to Manage Internal Cholesterol Levels under Nutritional Lipid Stress Conditions

et al. 2015

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Trypanosoma cruzi epimastigotes store high amounts of cholesterol and cholesteryl esters in reservosomes. These unique organelles are responsible for cellular digestion by providing substrates for homeostasis and parasite differentiation. Here we demonstrate that under nutritional lipid stress, epimastigotes preferentially mobilized reservosome lipid stocks, instead of lipid bodies, leading to the consumption of parasite cholesterol reservoirs and production of ergosterol. Starved epimastigotes acquired more LDL-NBD-cholesterol by endocytosis and distributed the exogenous cholesterol to their membranes faster than control parasites. Moreover, the parasites were able to manage internal cholesterol levels, alternating between consumption and accumulation. With normal lipid availability, parasites esterified cholesterol exhibiting an ACAT-like activity that was sensitive to Avasimibe in a dose-dependent manner. This result also implies that exogenous cholesterol has a role in lipid reservoirs in epimastigotes.

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“…ACAT inhibitors that did not have the expected result of reducing atherosclerotic plaques in clinical trials may find a new use in cholesterol-accumulating cancers. A new ACAT1-specific inhibitor was effective in killing glioma cells in in vitro studies (Bemlih, Poirier et al 2010). LXR pathway modulators that can increase cholesterol efflux and HDL-C levels without stimulating lipid biosynthesis in the liver, needed to treat cardiovascular disease and metabolic syndrome, may also be useful in cancer (Ratni, Blum-Kaelin et al 2009).…”

Section: Discussionmentioning

confidence: 99%

Lipoproteins and Cancer

Antalis¹,

Buhman²

2012

Lipoproteins - Role in Health and Diseases

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Acyl-coenzyme A: Cholesterol acyltransferase inhibitor Avasimibe affect survival and proliferation of glioma tumor cell lines

Cited by 78 publications

References 15 publications

A lipoprotein source of cholesteryl esters is essential for proliferation of CEM-CCRF lymphoblastic cell line

A lipoprotein source of cholesteryl esters is essential for proliferation of CEM-CCRF lymphoblastic cell line

Trypanosoma cruzi Epimastigotes Are Able to Manage Internal Cholesterol Levels under Nutritional Lipid Stress Conditions

Lipoproteins and Cancer

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