Avasimibe Encapsulated in Human Serum Albumin Blocks Cholesterol Esterification for Selective Cancer Treatment

Lee, Seung Young; Li, Junjie; tai, jien nee; Ratliff, Timothy L.; Park, Kinam; Cheng, Ji‐Xin

doi:10.1021/nn504025a

Cited by 83 publications

(67 citation statements)

References 76 publications

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“…Tumor growth was monitored weekly by IVIS imaging by detecting the luminescence signal in vivo . Avasimibe was prepared using a water-soluble formulation by complexing with human serum albumin (32) and intraperitoneally injected at a dose of 15 mg/kg per day. The results showed that avasimibe treatment for 4 weeks remarkably suppressed tumor size, as indicated by luminescence signal intensity (Fig.…”

Section: Resultsmentioning

confidence: 99%

Abrogating cholesterol esterification suppresses growth and metastasis of pancreatic cancer

et al. 2016

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Cancer cells are known to execute reprogramed metabolism of glucose, amino acids, and lipids. Here, we report a significant role of cholesterol metabolism in cancer metastasis. By employing label-free Raman spectromicroscopy, we found an aberrant accumulation of cholesteryl ester in human pancreatic cancer specimens and cell lines, mediated by acyl-CoA cholesterol acyltransferase-1 (ACAT-1) enzyme. Expression of ACAT-1 showed a correlation with poor patient survival. Abrogation of cholesterol esterification, either by an ACAT-1 inhibitor or by shRNA knockdown, significantly suppressed tumor growth and metastasis in an orthotopic mouse model of pancreatic cancer. Mechanically, ACAT-1 inhibition increased intracellular free cholesterol level, which was associated with elevated endoplasmic reticulum stress and caused apoptosis. Collectively, our results demonstrate a new strategy for treating metastatic pancreatic cancer by inhibiting cholesterol esterification.

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Section: Resultsmentioning

confidence: 99%

Abrogating cholesterol esterification suppresses growth and metastasis of pancreatic cancer

et al. 2016

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“…This led to apoptosis and the suppression of proliferation. Systemic treatment of avasimin notably suppressed tumor growth in mice and prolonged survival time 59 . Similarly, SOAT1 inhibition decreased cell proliferation and invasion in two tumor cell lines 60 .…”

Section: Soatmentioning

confidence: 98%

Role of de novo cholesterol synthesis enzymes in cancer

2020

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Despite extensive research in the cancer field, cancer remains one of the most prevalent diseases. There is an urgent need to identify specific targets that are safe and effective for the treatment of cancer. In recent years, cancer metabolism has come into the spotlight in cancer research. Lipid metabolism, especially cholesterol metabolism, plays a critical role in membrane synthesis as well as lipid signaling in cancer. This review focuses on the contribution of the de novo cholesterol synthesis pathway to tumorigenesis, cancer progression and metastasis. In conclusion, cholesterol metabolism could be an effective target for novel anticancer treatment.

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“…In prostate cancer, avasimibe treatment impairs the Wnt-β-catenin pathway and thus suppresses metastasis 111 . Application of avasimin, a nanomedicine version of avasimibe encapsulated with human serum albumin 112 , specifically induces cancer cell apoptosis and is effective in tumour xenograft models.…”

Section: Enhancement Of Cd8 T Cell Function and Inhibition Of The Regmentioning

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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Avasimibe Encapsulated in Human Serum Albumin Blocks Cholesterol Esterification for Selective Cancer Treatment

Cited by 83 publications

References 76 publications

Abrogating cholesterol esterification suppresses growth and metastasis of pancreatic cancer

Abrogating cholesterol esterification suppresses growth and metastasis of pancreatic cancer

Role of de novo cholesterol synthesis enzymes in cancer

Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities

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