Pharmacological blockade of cholesterol trafficking by cepharanthine in endothelial cells suppresses angiogenesis and tumor growth

Lyu, Junfang; Yang, Eun Ju; Head, Sarah A.; Ai, Nana; Zhang, Baoyuan; Wu, Changjie; Li, Ruo Jing; Liu, Yifan; Yang, Chen; Dang, Yongjun; Kwon, Ho Jeong; Ge, Wei; Liu, Jun O.; Shim, Joong Sup

doi:10.1016/j.canlet.2017.09.009

Cited by 61 publications

(70 citation statements)

References 55 publications

(62 reference statements)

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“…CEP inhibits VEGF-promoted tubule formation in HUVECs, an effect that is likely associated with the inhibition of VEGF and IL-8 expression involved in the blockade of NFκB activity (Harada et al, 2009). CEP was also found to inhibit angiogenesis in HUVEC and in zebrafish in a cholesterol-dependent manner, as mentioned above (Lyu et al, 2017).…”

Section: Inhibition Of Angiogenesismentioning

confidence: 69%

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Cepharanthine: An update of its mode of action, pharmacological properties and medical applications

2019

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A B S T R A C TBackground: Cepharanthine (CEP) is a drug used in Japan since the 1950s to treat a number of acute and chronic diseases, including treatment of leukopenia, snake bites, xerostomia and alopecia. It is the only approved drug for Human use in the large class of bisbenzylisoquinoline alkaloids. This natural product, mainly isolated from the plant Stephania cephalantha Hayata, exhibits multiple pharmacological properties including anti-oxidative, anti-inflammatory, immuno-regulatory, anti-cancer, anti-viral and anti-parasitic properties. Purpose: The mechanism of action of CEP is multifactorial. The drug exerts membrane effects (modulation of efflux pumps, membrane rigidification) as well as different intracellular and nuclear effects. CEP interferes with several metabolic axes, primarily with the AMP-activated protein kinase (AMPK) and NFκB signaling pathways. In particular, the anti-inflammatory effects of CEP rely on AMPK activation and NFκB inhibition. Conclusion: In this review, the historical discovery and development of CEP are retraced, and the key mediators involved in its mode of action are presented. The past, present, and future of CEP are recapitulated. This review also suggests new opportunities to extend the clinical applications of this well-tolerated old Japanese drug.

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Section: Inhibition Of Angiogenesismentioning

confidence: 69%

“…CEP can inhibit the endolysosomal trafficking of free-cholesterol and low-density lipoproteins, leading to the dissociation of mTOR from lysosomes and inhibition of its downstream signaling. This effect may directly contribute to the drug-induced inhibition of angiogenesis and tumor growth (Lyu et al, 2017).…”

Section: Interaction With Cell Membranesmentioning

confidence: 99%

Cepharanthine: An update of its mode of action, pharmacological properties and medical applications

2019

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“…As a consequence, cholesterol depletion or trafficking blockade hinders tumour growth and invasion in a variety of cancers [24][25][26][27] .…”

Section: Nature Metabolismmentioning

confidence: 99%

Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities

2020

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C holesterol is vital for the survival and growth of mammalian cells. More than a membrane constituent, cholesterol is a precursor to bile acids and steroid hormones, which can initiate or promote colon, breast and prostate cancers 1-3 . Cholesterol can also modulate signalling pathways involved in tumourigenesis and cancer progression by covalently modifying proteins including hedgehog and smoothened 4,5 , and by facilitating the formation of specialized membrane microdomains 6,7 . Brief overview of cholesterol metabolismEvery mammalian cell can synthesize cholesterol through the mevalonate pathway (Fig. 1a). Two acetyl-CoA molecules in the cytosol condense, thus forming acetoacetyl-CoA, which reacts with the third acetyl-CoA and yields 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). HMG-CoA is reduced to mevalonate by HMG-CoA reductase (HMGCR), the primary rate-limiting enzyme in cholesterol biosynthesis. A series of enzymatic reactions convert mevalonate to farnesyl pyrophosphate (FPP), a precursor of sterols and all non-sterol isoprenoids. The condensation of two FPP molecules to squalene commits the process to sterol production. FPP also gives rise to geranylgeranyl pyrophosphate (GGPP), and both FPP and GGPP can prenylate and activate several oncogenic proteins such as Ras 8 . Squalene is then oxidized by squalene epoxidase (SQLE) to 2,3-epoxysqualene, which is cyclized to lanosterol. In the next steps, lanosterol follows the Bloch pathway, the Kandutsch-Russell pathway or a hybrid pathway before it is finally converted to cholesterol.Beyond de novo cholesterol biosynthesis, most cells acquire cholesterol from low-density lipoprotein (LDL) taken up from the circulation via LDL receptor (LDLR)-mediated endocytosis 9 . Enterocytes absorb dietary cholesterol from the intestinal lumen in a process involving the cholesterol transporter NPC1L1, the clathrin adaptor NUMB and the adaptor protein LIMA1 (refs. 10-12 ). Cholesterol within the cell is dynamically transported, reaching the destined membranes for structural and functional needs 13 . Cholesterol in excess of the current cellular demand is either exported from the cell by ATP-binding cassette (ABC) transporters, Reprogrammed cholesterol metabolism in cancer cellsHallmark features of cancer cholesterol metabolism. As fastproliferating cells, cancer cells require high levels of cholesterol for membrane biogenesis and other functional needs. For example, the cholesterol-derived oncometabolite 6-oxo-cholestan-3β,5α-diol, which is enriched in patients with breast cancer, binds glucocorticoid receptors and subsequently promotes tumour growth 19 . In general, cholesterol metabolism substantially contributes to cancer progression, including cell proliferation, migration and invasion 20-23 .Cholesterol metabolism produces essential membrane components as well as metabolites with a variety of biological functions. In the tumour microenvironment, cell-intrinsic and cell-extrinsic cues reprogram cholesterol metabolism and consequently promote tumourigenesis. Cholesterol-de...

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“…It exhibits antimalarial, anti-viral, anti-inflammatory, anti-metastatic, and anti-cancer activities in various cell lines and animal models [772,[774][775][776]. Among its anti-cancer activities, CEP exhibits multiple pharmacological actions, including apoptosis and radiation sensitization, inhibition of angiogenesis and metastasis, and reversing MDR [776][777][778][779][780][781][782][783][784][785][786][787][788][789].…”

Section: Cepharanthine (Cep)mentioning

confidence: 99%

“…Therefore, this suggests that autophagy plays a dual role in cancer via different signaling routes. Moreover, CEP is suggested to be a potential anti-angiogenic agent, it blocks angiogenesis in endothelial cells, zebrafish and xenograft mice by inhibiting cholesterol trafficking [777]. It can also suppress metastasis in a highly metastatic tumor, cholangiocarcinoma, and markedly inhibit cell migration in human cholangiocarcinoma KKU-M213 and KKU-M214 cells [776].…”

Section: Cepharanthine (Cep)mentioning

confidence: 99%

Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine

et al. 2019

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Numerous natural products originated from Chinese herbal medicine exhibit anti-cancer activities, including antiproliferative, pro-apoptotic, anti-metastatic, anti-angiogenic effects, as well as regulate autophagy, reverse multidrug resistance, balance immunity, and enhance chemotherapy in vitro and in vivo. To provide new insights into the critical path ahead, we systemically reviewed the most recent advances (reported since 2011) on the key compounds with anti-cancer effects derived from Chinese herbal medicine (curcumin, epigallocatechin gallate, berberine, artemisinin, ginsenoside Rg3, ursolic acid, silibinin, emodin, triptolide, cucurbitacin B, tanshinone I, oridonin, shikonin, gambogic acid, artesunate, wogonin, β-elemene, and cepharanthine) in scientific databases (PubMed, Web of Science, Medline, Scopus, and Clinical Trials). With a broader perspective, we focused on their recently discovered and/or investigated pharmacological effects, novel mechanism of action, relevant clinical studies, and their innovative applications in combined therapy and immunomodulation. In addition, the present review has extended to describe other promising compounds including dihydroartemisinin, ginsenoside Rh2, compound K, cucurbitacins D, E, I, tanshinone IIA and cryptotanshinone in view of their potentials in cancer therapy. Up to now, the evidence about the immunomodulatory effects and clinical trials of natural anti-cancer compounds from Chinese herbal medicine is very limited, and further research is needed to monitor their immunoregulatory effects and explore their mechanisms of action as modulators of immune checkpoints.

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Pharmacological blockade of cholesterol trafficking by cepharanthine in endothelial cells suppresses angiogenesis and tumor growth

Cited by 61 publications

References 55 publications

Cepharanthine: An update of its mode of action, pharmacological properties and medical applications

Cepharanthine: An update of its mode of action, pharmacological properties and medical applications

Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities

Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine

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