Targeting cellular cholesterol for anticancer therapy

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 e...

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Bibliographic Details
Published in:The FEBS journal 2019-11, Vol.286 (21), p.4192-4208
Main Authors: Gu, Liang, Saha, Sourav Taru, Thomas, Jodie, Kaur, Mandeep
Format: Article
Language:English
Subjects:
Apoptosis
Biosynthesis
Breast cancer
Cancer
Cancer therapies
Cell division
Cell proliferation
Cholesterol
cholesterol depletion
cholesterol regulation
Clinical trials
Depletion
Drug resistance
metabolic and signalling pathways
Signal transduction
Signaling
statins
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Summary: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. Cholesterol imbalance has been reported in several studies to fuel cancer cell aggressiveness. There are two strategies in targeting cholesterol as a possible treatment for cancer; (a) inhibiting cholesterol synthesis using statins, thus blocking downstream proliferative pathways and (b) cholesterol‐depleting agents to reduce excess cholesterol and maintain cholesterol homeostasis, thereby halting cancer cell growth.
ISSN:1742-464X
1742-4658
DOI:10.1111/febs.15018