Recent advancements in the understanding of cholesterol metabolism have opened up new avenues for cancer therapy. This article explores how natural compounds derived from Traditional Chinese Medicine (TCM) can modulate cholesterol pathways, offering potential therapeutic strategies against various types of cancers. By targeting key processes in cholesterol biosynthesis, uptake, efflux, and esterification, these compounds may provide a safer and more effective alternative to existing treatments.

The review highlights the critical role of cholesterol in tumor development and identifies several promising TCM-derived substances that interfere with cholesterol-related mechanisms. These include inhibiting enzymes involved in cholesterol production, blocking exogenous cholesterol absorption, enhancing cholesterol export, and preventing its conversion into harmful derivatives within cancer cells. Although further research is needed, initial findings suggest significant potential for these natural products as anticancer agents.

Cholesterol Biosynthesis and Uptake: Targeting Key Processes

Natural compounds extracted from plants are being investigated for their ability to disrupt cholesterol synthesis and intake in cancer cells. These processes, essential for tumor growth, involve complex enzymatic reactions and transport proteins. By interfering with sterol-regulatory pathways, certain TCM-derived molecules demonstrate promising antitumor effects.

For instance, compounds like artesunate and gypenoside L inhibit cholesterol production by targeting sterol-regulatory element binding protein 2 (SREBP2). Curcumin, sourced from turmeric, reduces SREBP2 activity while also affecting niemann-pick type C1-like 1 (NPC1L1), a protein crucial for cholesterol uptake. Isoglycyrrhizin, another flavonoid, effectively downregulates NPC1L1 expression without causing significant toxicity. Additionally, alpineisoflavone suppresses HMGCR-mediated cholesterol biosynthesis by modulating androgen receptor expression. Together, these findings underscore the potential of TCM compounds in combating cancer through metabolic intervention.

Enhancing Cholesterol Efflux and Blocking Esterification

Efforts to enhance cholesterol efflux and prevent its esterification represent innovative strategies in cancer treatment. By promoting the removal of cholesterol from cancer cells and inhibiting its storage as cholesteryl esters, researchers aim to deprive tumors of vital resources needed for proliferation. Several TCM-derived compounds show efficacy in this regard.

Celastrol, obtained from Tripterygium wilfordii, increases the expression of ATP-binding cassette transporter A1 (ABCA1), thereby facilitating cholesterol export from tumor tissues. Manzamine A targets acyl-coenzyme A and cholesterol acyltransferase (ACAT2), reducing cholesterol esterification and curtailing tumor growth. Similarly, avasimibe, an ACAT inhibitor, has demonstrated anti-cancer properties in murine melanoma models by lowering cholesteryl ester levels. Furthermore, the activation of liver X receptor (LXR) pathways by small molecules enhances cholesterol efflux, contributing to the suppression of tumor progression. These discoveries highlight the multifaceted potential of TCM compounds in disrupting cholesterol metabolism for cancer therapy.