Fluvastatin suppresses the proliferation, invasion, and migration and promotes the apoptosis of endometrial cancer cells by upregulating Sirtuin 6 (SIRT6)

Cai, Yu; Zhao, Feng

doi:10.1080/21655979.2021.2009415

Cited by 4 publications

(4 citation statements)

References 29 publications

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“…Although the inhibitory effects of fluvastatin have been shown in various cancers, the underlying molecular mechanisms are not well understood and complex, including Sirtuin 6 upregulation, HMG-CoA reductase inhibition, Ras isoprenylation and inhibition of Akt phosphorylation. 13,31,32 Similar to atorvastatin’s action in glioblastoma, 14 our mechanistic studies confirm that fluvastatin acts on glioblastoma via suppressing Ras activity, and furthermore that this is prenylation-dependent. Aberrant Ras activation due to either overexpression or mutation plays a pivotal role in regulating proliferation, survival, differentiation and signal transduction in glioblastoma.…”

Section: Discussionsupporting

confidence: 61%

Overcoming chemoresistance in glioblastoma by fluvastatin via prenylation-dependent inhibition of Ras signaling

et al. 2022

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The resistance of glioblastoma to chemotherapy remains a significant clinical problem. Targeting alternative pathways such as protein prenylation is known to be effective against many cancers. Fluvastatin is a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl- CoA (HMG-CoA) reductase, thereby inhibits prenylation. We demonstrate that fluvastatin alone effectively inhibits proliferation and induces apoptosis in multiple human glioblastoma cell lines. The combination index analysis shows that fluvastatin acts synergistically with common chemotherapy drugs for glioblastoma: temozolomide and irinotecan. We further show that fluvastatin acts on glioblastoma through inhibiting prenylation-dependent Ras activation. The combination of fluvastatin and low dose temozolomide resulted in remarkable inhibition of glioblastoma tumor in mice throughout the whole treatment duration without causing toxicity. Such combinatorial effects provide the basis for utilizing these FDA-approved drugs as a potential clinical approach in overcoming resistance and improving glioblastoma treatment.

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Section: Discussionsupporting

confidence: 61%

Overcoming chemoresistance in glioblastoma by fluvastatin via prenylation-dependent inhibition of Ras signaling

et al. 2022

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“…Glucose availability–specifically, high glucose-mediated increases in reactive oxygen species–has been shown to influence cNCC apoptosis 9 . Furthermore, studies have shown both fatostatin and fluvastatin, a direct inhibitor of HMG-CoA reductase, to possess apoptotic effects 30 – 33 . We were therefore interested in examining the effect of cholesterol inhibitors on cNCC susceptibility to apoptosis under varying glucose conditions.…”

Section: Resultsmentioning

confidence: 99%

Cholesterol biosynthesis modulates differentiation in murine cranial neural crest cells

Pascual

Icyuz

Karmaus

et al. 2023

Sci Rep

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Cranial neural crest cells (cNCC) are a multipotent embryonic cell population that give rise to a diverse set of cell types. These cells are particularly vulnerable to external metabolic stressors, as exemplified by the association between maternal hyperglycemia and congenital malformations. We were interested in studying the effect of various concentrations of glucose and pyruvate on cNCC metabolism, migration, and differentiation using an established murine neural crest cell model (O9-1). We unexpectedly observed a pattern of gene expression suggestive of cholesterol biosynthesis induction under glucose depletion conditions in O9-1 cells. We further showed that treatment with two different cholesterol synthesis inhibitors interfered with cell migration and differentiation, inhibiting chondrogenesis while enhancing smooth muscle cell differentiation. As congenital arhinia (absent external nose), a malformation caused by mutations in SMCHD1, appears to represent, in part, a defect in cNCC, we were also interested in investigating the effects of glucose and cholesterol availability on Smchd1 expression in O9-1 cells. Smchd1 expression was induced under high glucose conditions whereas cholesterol synthesis inhibitors decreased Smchd1 expression during chondrogenesis. These data highlight a novel role for cholesterol biosynthesis in cNCC physiology and demonstrate that human phenotypic variability in SMCHD1 mutation carriers may be related, in part, to SMCHD1’s sensitivity to glucose or cholesterol dosage during development.

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“…Fluvastatin, the first fully synthetic HMG-CoA reductase (HMGCR) inhibitor, is reported to prevent the growth and spread of certain malignancies ( Cai and Zhao, 2021 ). Fluvastatin prevents trained immunity by downregulating H3K4me3 and blocking the production of proinflammatory cytokines ( Arts et al, 2016a ).…”

Section: Inhibitors Of Targeting Trained Immunitymentioning

confidence: 99%

Trained immunity in monocyte/macrophage: Novel mechanism of phytochemicals in the treatment of atherosclerotic cardiovascular disease

Wang

Liu²,

Hu³

et al. 2023

Front. Pharmacol.

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Atherosclerosis (AS) is the pathology of atherosclerotic cardiovascular diseases (ASCVD), characterized by persistent chronic inflammation in the vessel wall, in which monocytes/macrophages play a key role. It has been reported that innate immune system cells can assume a persistent proinflammatory state after short stimulation with endogenous atherogenic stimuli. The pathogenesis of AS can be influenced by this persistent hyperactivation of the innate immune system, which is termed trained immunity. Trained immunity has also been implicated as a key pathological mechanism, leading to persistent chronic inflammation in AS. Trained immunity is mediated via epigenetic and metabolic reprogramming and occurs in mature innate immune cells and their bone marrow progenitors. Natural products are promising candidates for novel pharmacological agents that can be used to prevent or treat cardiovascular diseases (CVD). A variety of natural products and agents exhibiting antiatherosclerotic abilities have been reported to potentially interfere with the pharmacological targets of trained immunity. This review describes in as much detail as possible the mechanisms involved in trained immunity and how phytochemicals of this process inhibit AS by affecting trained monocytes/macrophages.

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Fluvastatin suppresses the proliferation, invasion, and migration and promotes the apoptosis of endometrial cancer cells by upregulating Sirtuin 6 (SIRT6)

Cited by 4 publications

References 29 publications

Overcoming chemoresistance in glioblastoma by fluvastatin via prenylation-dependent inhibition of Ras signaling

Overcoming chemoresistance in glioblastoma by fluvastatin via prenylation-dependent inhibition of Ras signaling

Cholesterol biosynthesis modulates differentiation in murine cranial neural crest cells

Trained immunity in monocyte/macrophage: Novel mechanism of phytochemicals in the treatment of atherosclerotic cardiovascular disease

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