Traditional Chinese medicine targets cholesterol metabolism for cancer treatment

Traditional Chinese medicine targets cholesterol metabolism for cancer treatment

Traditional Chinese medicine offers promising natural compounds that modulate cholesterol metabolism and introduce new therapeutic avenues for cancer treatment.

In a recently published study inActa Pharmakologica Sinica,Researchers review the four major cholesterol metabolism processes and how natural products in traditional Chinese medicine (TCM) can modulate cholesterol metabolism for cancer treatment.

The role of cholesterol levels in cancer

Within the cell membrane, cholesterol, an amphiphilic sterol molecule, maintains the integrity of this structure by supporting its fluidity while regulating the organization of ion channel function and membrane protein. Cholesterol homeostasis is achieved by maintaining balanced cholesterol levelsde novoBiosynthesis, uptake, efflux and esterification.

Cholesterol also supports tumor cell proliferation by regulating signal transduction and membrane biogenesis. Previous studies have reported that alterations in cholesterol homeostasis are involved in cancer progression. For example, high expression of adenosine triphosphespaste (ATP)-binding cassette transporter A1 (ABCA1) leads to cholesterol efflux and increases membrane fluidity, contributing to triple breast cancer (TNBC) metastasis.

Existing therapeutics that target cholesterol metabolism, including certain enzyme inhibitors and transport protein modulators, have been evaluated for their potential anti-neoplastic effects. However, these treatments are associated with limited long-term effectiveness in certain patient populations as well as an increased risk of side effects and drug resistance.

Therefore, there remains an urgent need to identify new therapeutic approaches that can overcome these challenges. For example, TCM, which is typically well tolerated, natural products have been studied for their ability to regulate cholesterol metabolism to treat cancer.

In fact, a recent study reported that TCM-derived compounds such as quercetin can reduce cholesterol synthesis by activating adenosine monophosphate-activated protein kinase (AMPK) and inhibiting 3-hydroxy-3-methylglutarylcoenzyme A reductase A reductase A reductase activity.

Targeting cholesterol biosynthesis

The majority of cells, with the exception of mature red blood cells and brain tissue, can synthesize cholesterol levels. Cholesterol synthesis is an ATP-intensive process involving nearly thirty enzymatic reactions and over fifteen proteins. Therefore, any disruptions in genes or enzymes involved in cholesterol homeostasis may promote cancer.

Sterol regulatory element binding protein 2 (SREBP2), 3-hydroxy-3-methylglutaryl conenzyme A reductase (HMGCR), and squalene epoxidase (SQLE) are key molecules involved in cholesterol biosynthesis that can be inhibited by natural products.

For example, SREBP2 can be targeted by artesunate (ART), which is a derivative of artemisinin, to inhibit cholesterol synthesis. Gypenoside L can also regulate the methyl-valproate (MVA) pathway by targeting SREBP2, which mediates cholesterol biosynthesis and supports liver tumor stem cell growth.

Natural products such as emodin extracted from the roots ofReynou Tria japonicaand Osthole, which is obtained fromCnidium Monnierisynergistically reduce SREBP2 activity through their involvement in nuclear factor κB (NF-κB), with nitrogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt). However, additional research is needed to elucidate their exact mechanism of action.

Alpine isoflavone (AIF) also exhibits anticancer properties through its ability to inhibit androgen receptor (AR) expression, thereby targeting HMGCR-mediated cholesterol biosynthesis.

Targeting cholesterol intake

Cancer cells rely on exogenous cholesterol intake to support rapid proliferation. This uptake is mediated by proteins such as Niemann-Pick type C1-like 1 (NPC1L1) and low-density lipoprotein receptor (LDLR). However, ezetimibe, an approved NPC1L1 inhibitor typically used to treat hypercholesterolemia, is associated with limited anticancer efficacy.

Curcumin, a natural compound extracted from turmeric, exhibits activity against lung, breast and colon cancers. These anticancer effects are attributed to increased intracellular cholesterol transport, a process that relies on the activation of transient receptor potential A1 (TRPA1). The scope also reduces SREBP2 and NPC1L1 levels in a dose-dependent manner.

Isoglycyrrhizin is a chalcone-structured flavonoid extracted fromGlycyrrhiza uralensisThis downregulates NPC1L1 expression and completely inhibits cholesterol uptake with negligible cytotoxicity. Despite these observations in additionIn vivoExperiments are needed to determine their safety and effectiveness.

Chrysanthemon is a potent NPC1L1 inhibitor extracted fromTanacetum parathenium.So far that oneThe anticancer activity of chrysantemone remains unclear.

Targeting cholesterol efflux

Several studies have demonstrated the role of ABC transporter and liver X receptor (LXR) in cholesterol efflux. These studies have also demonstrated the effectiveness of small molecules to enhance these processes to achieve anticancer effects.

Celastrol, a triterpenoid compound extracted fromTripterygium Wilfordii,exhibits anti-cancer activity by inhibiting the growth of clear cell renal carcinoma (CCRC) rexenograft tumors in a dose-dependent manner. Celastrol also upregulates ABCA1 expression in tumor tissues, which promotes cholesterol efflux by improving lipid metabolism and reducing cholesterol accumulation in tumor cells.

Targeting cholesterol esterification

Cholesterol levels are converted into cholesteryl esters (CES) by acyl-coenzyme A and cholesterol acyltransferase (ACAT). Accumulation of CES provides tumor cells with an abundance of cholesterol levels to maintain membrane formation, fluidity and stability. CE voltage is also associated with loss of tumor suppressor factor phosphatase and tensin homolog (PTEN).

Manzamine A is another bioactive compound that targets ACAT2 to inhibit cholesterol esterification, thereby promoting anticancer activity. YoungestIn vivoStudies using a mouse melanoma model confirmed the role of avasimibe as an ACAT inhibitor, reducing CES levels to promote anti-cancer effects.

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