Targeting cellular cholesterol for anticancer therapy

Abstract

Cholesterol dyshomeostasis in cancer cells leads to intracellular cholesterol accumulation, which imparts drug resistance and allows these cells to evade apoptotic signalling processes and maintain continuous cell division and proliferation. Therefore, cholesterol lowering in cancer cells has been envisaged as a potential anticancer strategy. In this direction, two therapeutic strategies have been proposed: (a) to inhibit the biosynthesis of cholesterol in the cells and (b) to deplete excess cholesterol from cancer cells. In the first phase of this review, we collate the cancer signalling pathways (particularly in breast cancer) that are perturbed by cholesterol dyshomeostasis and highlight recent drug discovery efforts to develop cholesterol‐lowering compounds, some of which are currently under clinical trials. In the second phase, based on the analysis of the available scientific evidence, we conceptualize and argue that the depletion of excess cholesterol could sensitize cancer cells to available therapeutics and may also help to alleviate cancer drug resistance.

Falcarindiol Purified From Carrots Leads to Elevated Levels of Lipid Droplets and Upregulation of Peroxisome Proliferator-Activated Receptor-γ Gene Expression in Cellular Models

“…The anticancer function of ABCA1 in human cancer cells has been demonstrated and is probably related to its ability to decrease the content of mitochondrial cholesterol resulting in the release of cell death-promoting molecules ( Smith and Land, 2012 ). This is also consistent with the fact that tumors show increased levels of cholesterol compared to normal tissue and therefore cholesterol lowering in cancer cells has been suggested as a potential anticancer strategy ( Smith and Land, 2012 ; Gu et al, 2019 ).…”

“…The cholesteryl esters are usually stored in lipid droplets (LD) serving as a readily available reservoir for neutral lipids ( Tirinato et al, 2017 ; Cruz et al, 2020 ). Although an accumulation of lipid droplets in cancer cells can lead to increased proliferation and aggressiveness of tumors ( Gu et al, 2019 ; Cruz et al, 2020 ), it appears to depend on the total amount of cholesterol accumulated in cancer cells. It has for example been shown that some polyunsaturated fatty acids, such as docosahexaenoic acid, cause a redistribution of cholesterol from intracellular compartments (mitochondria and ER) to polyunsaturated-enriched lipid droplets but not in an increase of total cholesterol ( Jakobsen et al, 2008 ).…”

Impact of Plasma Membrane Domains on IgG Fc Receptor Function

“…Based on the crucial role of the plasma membrane and its organized domains for many cellular processes, drugs altering the plasma membrane lipid composition, structure or function have been developed for, e.g., malignant, metabolic, cardiovascular, or neurodegenerative disorders (218,219). One example for such a drug, the compound azurin, has recently been shown to decrease the plasma membrane order of cancer cells upon uptake thereby attenuating cell signaling and subsequently tumor cell growth (220).…”

New Insights Into Targeting Membrane Lipids for Cancer Therapy

“…There is no doubt that this recent progress in understanding cholesterol homeostasis and metabolism set the basis for the development of current therapies based on cholesterol and lipids targeting. A decrease in membrane cholesterol has been observed to have beneficial effects against different pathological condition including cancer and neurodegenerative diseases ( Simons et al, 1998 ; Canevari and Clark, 2007 ; Guardia-Laguarta et al, 2009 ; Barros et al, 2018 ; Chen et al, 2018 ; Gu et al, 2019 ). Cholesterol-targeting can be achieved via cholesterol depletion, sequestration or inhibition of synthesis.…”