Amelioration of Hypercholesterolemia by an EGFR Tyrosine Kinase Inhibitor in Mice with Liver-Specific Knockout of Mig-6

Lee, Jun Choul; Choung, Sorim; Kim, Ji Min; Joung, Kyong Hye; Kim, Koon Soon; Kim, Hyun Jin; Jeong, Jae Wook; Rhee, Sang Dal; Ku, Bon Jeong

doi:10.1371/journal.pone.0114782

Cited by 17 publications

(10 citation statements)

References 27 publications

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“…7 We also observed that serum cholesterol levels were decreased by gefitinib treatment in these mice. 18 Interestingly, in our current study, serum cholesterol levels were decreased more in patients with EGFR activating mutations than in those without EGFR mutations. These data support the aforementioned results obtained in gefitinib-treated Mig-6 knockout mice.…”

Section: Discussioncontrasting

confidence: 41%

Treatment with Gefitinib, an Epidermal Growth Factor Receptor Inhibitor, Decreases Serum Cholesterol in Patients with Lung Cancer

Kang

Kim

Joung

et al. 2016

KJO

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Background: Statins are used to treat hypercholesterolemia; however, major cardiovascular events are decreased only 30% by statin treatment. Treatment with an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been reported to decrease serum glucose levels and improved insulin sensitivity in mice and humans, but there was no study in serum cholesterol levels. This study examined the effect of gefitinib, an EGFR tyrosine kinase inhibitor, on cholesterol metabolism in humans. Methods: We retrospectively reviewed the medical records of 299 patients with primary lung cancer treated with gefitinib for ≥ 1 month and 72 patients with other treatments. Serum cholesterol, serum triglycerides, and body mass index were measured before and after treatment. The changes in serum cholesterol, serum triglycerides, and body mass index were compared between the gefitinib treatment group and the control group and were also analyzed according to the presence or absence of EGFR mutations. Results: Serum cholesterol levels decreased significantly from 178.9 to 164.4 mg/dL after 1-month of gefitinib treatment. A total of 54 of the 299 patients underwent examination for the presence of the EGFR mutations. Serum cholesterol was significantly decreased in the group with the activating EGFR mutation (Δ = 21.3 mg/dL) compared to that of those without the EGFR mutation (Δ =-3.1 mg/dL) after treatment with gefitinib. In contrast, there was no significantly difference between the two groups in control patients. Conclusion: Treatment with gefitinib decreased serum cholesterol in lung cancer patients, particularly in those with activating mutations in EGFR. These data suggest that EGFR tyrosine kinase inhibitors provide a novel and attractive strategy for the treatment of hypercholesterolemia.

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Section: Discussioncontrasting

confidence: 41%

Treatment with Gefitinib, an Epidermal Growth Factor Receptor Inhibitor, Decreases Serum Cholesterol in Patients with Lung Cancer

Kang

Kim

Joung

et al. 2016

KJO

Self Cite

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“…Statins show synergistic anti-cancer effects with EGFR inhibitors [27]. Recently, the EGFR inhibitor gefitinib was reported to be effective for the treatment of cancer in highfat-diet-fed Mig-6 d/d mice [28], indicating a possible linkage between EGFR and cholesterol. Therefore, we examined whether EGFR activity is associated with HMG-CR downregulation in doxorubicin-treated cells.…”

Section: Hmg-cr Downregulation Through the Egfr/src Pathway Is Criticmentioning

confidence: 99%

Anti-cancer effect of doxorubicin is mediated by downregulation of HMG-Co A reductase via inhibition of EGFR/Src pathway

Yun

Lee

Shim

et al. 2019

Laboratory Investigation

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Doxorubicin is a widely used DNA damage-inducing anti-cancer drug. However, its use is limited by its dose-dependent side effects, such as cardiac toxicity. Cholesterol-lowering statin drugs increase the efficacy of some anti-cancer drugs. Cholesterol is important for cell growth and a critical component of lipid rafts, which are plasma membrane microdomains important for cell signaling. 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMG-CR) is a critical enzyme in cholesterol synthesis. Here, we show that doxorubicin downregulated HMG-CR protein levels and thus reduced levels of cholesterol and lipid rafts. Cholesterol addition attenuated doxorubicin-induced cell death, and cholesterol depletion enhanced it. Reduction of HMG-CR activity by simvastatin, a statin that acts as an HMG-CR inhibitor, or by siRNAmediated HMG-CR knockdown enhanced doxorubicin cytotoxicity. Doxorubicin-induced HMG-CR downregulation was associated with inactivation of the EGFR-Src pathway. Furthermore, a high-cholesterol-diet attenuated the anti-cancer activity of doxorubicin in a tumor xenograft mouse model. In a multivulva model of Caenorhabditis elegans expressing an active-EGFR mutant, doxorubicin decreased hyperplasia more efficiently in the absence than in the presence of cholesterol. These data indicate that EGFR/Src/HMG-CR is a new pathway mediating doxorubicin-induced cell death and that cholesterol control could be combined with doxorubicin treatment to enhance efficacy and thus reduce side effects.

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“…Further continuing the study, the biological activity spectrum of the compounds was studied using 'PASS' to know whether the compounds have the potential to be pharmacologically active or not. Biological activities like free radical scavenging, antioxidants, lipid peroxidase and kinase inhibitors influence hypercholesterolemia (Charles-Schoeman et al, 2015, Lee et al,2014). Hence, from the biological spectrum of the compounds, the Pa and Pi values of the mentioned biological activities are listed for the compounds present in C.album in Table3.…”

Section: Resultsmentioning

confidence: 99%

Molecular docking studies of Chenopodium album Linn with Lanosterol synthase enzyme

Madhuri¹,

Goteti

2021

JANS

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Cardiovascular diseases (CVD) are the major cause of death among people across the globe. Hypercholesterolemia is one of the major contributing factors for CVD. Molecules that bind with Lanosterol synthase enzyme, can be potential drug targets. Statin group of compounds like Simvastatin, cerivastatin, Atorvastatin etc., used for treating hypercholesterolemia have side effects and hence there is a growing demand for plant derived flavonoids. This work focusses on studying the compounds quercetin-3-O-(2??,6??-di-O-?-l-rhamnopyranosyl)-?-d-glucopyranoside, kaempferol-3-O-(2??,6??-di-O-?-l-rhamnopyranosyl)-?-d-glucopyranoside, rutin; quercetin-3-O-?-d-glucopyranoside (Iso quercetin); and kaempferol-3-O-?-d-glucopyranoside (Astragalin) present in Chenopodium album Linn to inhibit Lanosterol synthase. Bioactivity score, drug likeness character was assessed in silico. Based on bioactivity spectrum, it is observed that the molecules are biologically active and the probability of these compounds to be biologically active is ranging from 0.784 to 0.992, suggesting that these compounds are effective for treating hypercholesterolemia. In the molecular docking studies, the compounds binding affinity score was in agreement that the molecules have the potential to be used as an alternative to the statin group of compounds in treating cholesterol.

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Amelioration of Hypercholesterolemia by an EGFR Tyrosine Kinase Inhibitor in Mice with Liver-Specific Knockout of Mig-6

Cited by 17 publications

References 27 publications

Treatment with Gefitinib, an Epidermal Growth Factor Receptor Inhibitor, Decreases Serum Cholesterol in Patients with Lung Cancer

Treatment with Gefitinib, an Epidermal Growth Factor Receptor Inhibitor, Decreases Serum Cholesterol in Patients with Lung Cancer

Anti-cancer effect of doxorubicin is mediated by downregulation of HMG-Co A reductase via inhibition of EGFR/Src pathway

Molecular docking studies of Chenopodium album Linn with Lanosterol synthase enzyme

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