Simvastatin aggravates impaired autophagic flux in NSC34-hSOD1G93A cells through inhibition of geranylgeranyl pyrophosphate synthesis

Qi, Wang; Liu, Yan; Liu, Yaling; Zhou, Xiaomeng; Li, Rui; Bai, Lin; Chen, Juan; Nie, Xiangyu

doi:10.1016/j.neuroscience.2019.04.034

Cited by 11 publications

(11 citation statements)

References 47 publications

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“…As an efficacious and commonly used chemotherapeutic agent, doxorubicin induces incomplete autophagy‐mediated cardiotoxicity in cardiomyocytes by blocking lysosome acidification and lysosomal function 46 . Simvastatin induces incomplete autophagy by inhibiting GGPP synthesis leading to cytotoxicity in NSC34‐hSOD1G93A cells 189 . Haloperidol and clozapine, two antipsychotic agents, blocked formation of autophagolysosomes in rat primary neurons 190 .…”

Section: Toxic Substances Induced Incomplete Autophagymentioning

confidence: 99%

Incomplete autophagy: Trouble is a friend

Zhang

Cao

Qiu

et al. 2022

Medicinal Research Reviews

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Incomplete autophagy is an impaired self‐eating process of intracellular macromolecules and organelles in which accumulated autophagosomes do not fuse with lysosomes for degradation, resulting in the blockage of autophagic flux. In this review, we summarized the literature over the past decade describing incomplete autophagy, and found that different from the double‐edged sword effect of general autophagy on promoting cell survival or death, incomplete autophagy plays a crucial role in disrupting cellular homeostasis, and promotes only cell death. What matters is that incomplete autophagy is closely relevant to the pathogenesis and progression of various human diseases, which, meanwhile, intimately linking to the pharmacologic and toxicologic effects of several compounds. Here, we comprehensively reviewed the latest progress of incomplete autophagy on molecular mechanisms and signaling pathways. Moreover, implications of incomplete autophagy for pharmacotherapy are also discussed, which has great relevance for our understanding of the distinctive role of incomplete autophagy in cellular physiology and disease. Consequently, targeting incomplete autophagy may contribute to the development of novel generation therapeutic agents for diverse human diseases.

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Section: Toxic Substances Induced Incomplete Autophagymentioning

confidence: 99%

Incomplete autophagy: Trouble is a friend

Zhang

Cao

Qiu

et al. 2022

Medicinal Research Reviews

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“…Liang et al [28] Simvastatin + Tamoxifen Lipophilic Downregulates expression of MCM7 leading to DNA damage in tamoxifen-resistant cells Liu et al [31] Simvastatin Lipophilic Reduces isoprenoid intermediates of the mevalonate pathway Reduces activity of Rho GTPases, Rac1 and Cdc42 Inhibits ERK1/2 pathway, which leads to activation of SASP Moriai et al [35] Lovastatin + Tamoxifen Lipophilic Downregulates survivin protein expression, which increases sensitivity to tamoxifen-induced apoptosis Kusama et al [38] Fluvastatin Lipophilic Inhibition of Rho A and Rho C membrane localization, thereby impairing cancer cell migration and invasion into the endothelial cell layer Liu et al [39] Fatostatin + Tamoxfen -Inhibitors of SREBP pathway resulting in decreased tumor cell invasion Degradation of ER protein PI3K-AKT-mTOR signaling disruption leading to apoptosis and autophagy Enhance tamoxifen-induced apoptosis and autophagy Enhanced tamoxifen-induced cell cycle arrest Iizuka-Ohashi et al [40] Fluvastatin Lipophilic Suppression of AKT activation, which decreases apoptotic resistance to MEK inhibitors Miettinen et al [44] Atorvastatin Lipophilic Induces accumulation of autophagosomes and decreased autophagic flux Shojaei et al [45] Simvastatin + Temozolomide Lipophilic Blocks autophagolysosome formation and increased proapoptotic cell death Misirkic et al [46] Simvastatin Lipophilic Upregulation of autophagolysosome-associated LC3-II indicating induction of autophagy Toepfer et al [47] Atorvastatin Lipophilic Upregulation of autophagolysosome-associated LC3-II indicating induction of autophagy Qi et al [48] Simvastatin Lipophilic Upregulation of autophagolysosome-associated LC3-II indicating induction of autophagy progression [27] . SVA has been shown to downregulate both Rb and MCM7 in two tamoxifen-resistant breast cancer cell lines, MCF7 and T47D, thereby leading to DNA damage.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

“…However, an increase in LC3II levels and autophagosomes can be seen upon inhibition of autophagic flux [ 47 ] . Simvastatin has also been shown to induce cytoplasmic accumulation of autophagic vacuoles, which was reversed by the addition of farnesyl and GGPP in a model of amyotrophic lateral sclerosis [ 48 ] .…”

Section: Autophagy and Statinsmentioning

confidence: 99%

Statins and endocrine resistance in breast cancer

Hyder¹,

Martí²,

Nasrazadani³

et al. 2021

CDR

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Most breast cancers are hormone-receptor positive (HR + ). However, more women eventually die from HR + breast cancer than from either HER2 + or triple negative breast cancer. Endocrine therapies continue to be the mainstay of treatment. In 40% of these cases, recurrences in early-stage disease and progression in the metastatic setting are largely a function of the development of endocrine resistance. A multitude of mediators and pathways have been associated with endocrine resistance in breast cancer including the mevalonate pathway, which is integral to cholesterol biosynthesis. The mevalonate pathway and the downstream activation of associated cytoplasmic pathways including PI3K-AKT-mTOR and RAS-MEK-ERK have been known to affect cancer cell proliferation, cell survival, cell invasion, and metastasis. These are important mechanisms leading to the inevitable development of endocrine resistance in HR + breast cancer. Statins are a class of drugs that inhibits HMG-CoA reductase, an enzyme in the mevalonate pathway that plays a central role in cholesterol production. In vitro and in vitro studies suggest that the role of statins in blocking the mevalonate pathway effectively disrupts downstream pathways involved in estrogen receptor expression and cellular processes such as cell survival, proliferation, stress, cell cycle, inhibition of apoptosis, and autophagy. Overcoming these key mechanisms heralds a role for statins in the prevention of endocrine resistance.

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“…Evidence has associated the etiopathogenesis of neurodegenerative disorders to aging as well as impairments in the autophagy pathways [ 101 , 102 ]. In patients with ALS, there is a motor neuron death, and simvastatin has been shown to suppress the GGPP synthesis, develop autophagic vacuoles, and decrease LC3II/I levels, which results in reduced autophagy in the neurons and ameliorates disease manifestations [ 103 ]. Rosuvastatin was shown to provide therapeutic neuroprotective effects in cerebral ischemic/reperfusion injury [ 104 ].…”

Section: Neuroprotective Effects Of Statinsmentioning

confidence: 99%

Implications on the Therapeutic Potential of Statins via Modulation of Autophagy

Gorabi

Kiaie

Aslani

et al. 2021

Oxidative Medicine and Cellular Longevity

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Statins, which are functionally known as 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) inhibitors, are lipid-lowering compounds widely prescribed in patients with cardiovascular diseases (CVD). Several biological and therapeutic functions have been attributed to statins, including neuroprotection, antioxidation, anti-inflammation, and anticancer effects. Pharmacological characteristics of statins have been attributed to their involvement in the modulation of several cellular signaling pathways. Over the past few years, the therapeutic role of statins has partially been attributed to the induction of autophagy, which is critical in maintaining cellular homeostasis and accounts for the removal of unfavorable cells or specific organelles within cells. Dysregulated mechanisms of the autophagy pathway have been attributed to the etiopathogenesis of various disorders, including neurodegenerative disorders, malignancies, infections, and even aging. Autophagy functions as a double-edged sword during tumor metastasis. On the one hand, it plays a role in inhibiting metastasis through restricting necrosis of tumor cells, suppressing the infiltration of the inflammatory cell to the tumor niche, and generating the release of mediators that induce potent immune responses against tumor cells. On the other hand, autophagy has also been associated with promoting tumor metastasis. Several anticancer medications which are aimed at inducing autophagy in the tumor cells are related to statins. This review article discusses the implications of statins in the induction of autophagy and, hence, the treatment of various disorders.

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Simvastatin aggravates impaired autophagic flux in NSC34-hSOD1G93A cells through inhibition of geranylgeranyl pyrophosphate synthesis

Cited by 11 publications

References 47 publications

Incomplete autophagy: Trouble is a friend

Incomplete autophagy: Trouble is a friend

Statins and endocrine resistance in breast cancer

Implications on the Therapeutic Potential of Statins via Modulation of Autophagy

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