Prevention of Hepatocellular Carcinoma by Statins: Clinical Evidence and Plausible Mechanisms

2019 ◽  
Vol 39 (02) ◽  
pp. 141-152 ◽  
Author(s):  
Gyuri Kim ◽  
Eun Seok Kang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Mevalonate Pathway ◽  
Therapeutic Potential ◽  
Experimental Studies ◽  
Term Treatment ◽  
Hmg Coa Reductase ◽  
Reductase Inhibitors ◽  
Novel Approach ◽  
Long Term Treatment ◽  
Coa Reductase

AbstractStatins, or 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are widely used to treat hypercholesterolemia for primary and secondary prevention of cardiovascular disease. Statins inhibit HMG-CoA reductase, the rate-limiting step in cholesterol synthesis, and modulate the downstream signaling of the mevalonate pathway. In addition to the primary effect, the antitumor effect of statins can be associated with mevalonate pathway-mediated and nonmevalonate pathway-mediated mechanisms, which improve endothelial function and lead to proapoptotic, antiproliferative, antiinflammatory, and antifibrotic properties. Statins are implicated in the improvement of metabolic status. Statins are orally available and safely and widely used for long-term treatment; they represent a novel approach for the prevention and treatment for hepatocellular carcinoma (HCC). Although several observational studies and experimental studies have revealed the preventive and therapeutic potential of statins for HCC treatment, further prospective interventional studies and randomized control trials are warranted to confirm these observations.

Cholesterol-modulating agents kill acute myeloid leukemia cells and sensitize them to therapeutics by blocking adaptive cholesterol responses

Blood ◽  
2003 ◽  
Vol 101 (9) ◽  
pp. 3628-3634 ◽  
Author(s):  
Henry Y. Li ◽  
Frederick R. Appelbaum ◽  
Cheryl L. Willman ◽  
Richard A. Zager ◽  
Deborah E. Banker
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Mevalonate Pathway ◽  
Hmg Coa Reductase ◽  
Cellular Cholesterol ◽  
Reductase Inhibitors ◽  
Acute Myeloid Leukemia Cells ◽  
Zaragozic Acid ◽  
Coa Reductase ◽  
Acute Myeloid

The mevalonate pathway produces many critical substances in cells, including sterols essential for membrane structure and isoprenoids vital to the function of many membrane proteins. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase is a rate-limiting enzyme in the mevalonate pathway. Because cholesterol is a product of this pathway, HMG-CoA reductase inhibitors (statins) are used to treat hypercholesterolemia. Statins are also toxic to several malignancies, including acute myeloid leukemia (AML). Although this toxicity has been attributed to the inhibition of Ras/Rho isoprenylation, we have previously shown that statin toxicity in primary AML cells (AMLs) does not correlate with Ras isoprenylation or with activating Ras mutations. In other studies, we have shown that hypoxic and oxidant injuries induce cholesterol increments in renal tubule cells and that statins sensitize these cells to injury by blocking protective cholesterol responses. We now demonstrate that exposing particular AMLs to radiochemotherapy induces much greater cellular cholesterol increments than those seen in similarly treated normal bone marrow. Treatment of these AMLs with mevastatin or zaragozic acid (which inhibits cholesterol synthesis but not isoprenoid synthesis) attenuates the cholesterol increments and sensitizes cells to radiochemotherapy. The extent of toxicity is affected by the availability of extracellular lipoproteins, further suggesting that cellular cholesterol is critical to cell survival in particular AMLs. Because zaragozic acid does not inhibit isoprenoid synthesis, these data suggest that cholesterol modulation is an important mechanism whereby statins exert toxic effects on some AMLs and that cholesterol modulators may improve therapeutic ratios in AML by impacting cholesterol-dependent cytoresistance.

A novel approach to the site specific delivery of potential HMG-CoA reductase inhibitors

1992 ◽  
Vol 2 (4) ◽  
pp. 285-290 ◽  
Author(s):  
Keith A. Menear ◽  
Dilip Patel ◽  
Valerie Clay ◽  
Colin Howes ◽  
Peter W. Taylor
Keyword(s):  
Hmg Coa Reductase ◽  
Site Specific ◽  
Reductase Inhibitors ◽  
Novel Approach ◽  
Hmg Coa Reductase Inhibitors ◽  
Coa Reductase

HMG-CoA reductase inhibitor simvastatin mitigates VEGF-induced “inside-out” signaling to extracellular matrix by preventing RhoA activation

2006 ◽  
Vol 291 (5) ◽  
pp. F995-F1004 ◽  
Author(s):  
Hanshi Xu ◽  
Lixia Zeng ◽  
Hui Peng ◽  
Sheldon Chen ◽  
Jonathan Jones ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Molecular Mechanisms ◽  
Mesangial Cells ◽  
Mevalonate Pathway ◽  
Cell Permeability ◽  
Hmg Coa Reductase ◽  
Rhoa Activation ◽  
Reductase Inhibitors ◽  
Hmg Coa Reductase Inhibitors ◽  
Coa Reductase

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors exert modulatory effects on a number of cell signaling cascades by preventing the synthesis of various isoprenoids derived from the mevalonate pathway. In the present study, we describe a novel pleiotropic effect of HMG-CoA reductase inhibitors, also commonly known as statins, on vascular endothelial growth factor (VEGF)-induced type IV collagen accumulation. VEGF is an angiogenic polypeptide that is also known to play a central role in endothelial cell permeability and differentiation. Recently, VEGF has also been implicated in promoting extracellular matrix (ECM) accumulation, although the precise signaling mechanism that mediates VEGF-induced ECM expansion remains poorly characterized. Elucidation of the mechanisms through which VEGF exerts its effect on ECM is clearly a prerequisite for both understanding the complex biology of this molecule as well as targeting VEGF in several pathological processes. To this end, this study explored the underlying molecular mechanisms mediating VEGF-induced ECM expansion in mesangial cells. Our findings show that VEGF stimulation elicits a robust increase in ECM accumulation that involves RhoA activation, an intact actin cytoskeleton, and β1- integrin activation. Our data also indicate that simvastatin, via mevalonate depletion, reverses VEGF-induced ECM accumulation by preventing RhoA activation.

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