RESUMEN
BACKGROUND: Metabolism reprogramming plays a vital role in glioblastoma (GBM) progression and recurrence by producing enough energy for highly proliferating tumor cells. In addition, metabolic reprogramming is crucial for tumor growth and immune-escape mechanisms. Epidermal growth factor receptor (EGFR) amplification and EGFR-vIII mutation are often detected in GBM cells, contributing to the malignant behavior. This study aimed to investigate the functional role of the EGFR pathway on fatty acid metabolism remodeling and energy generation. METHODS: Clinical GBM specimens were selected for single-cell RNA sequencing and untargeted metabolomics analysis. A metabolism-associated RTK-fatty acid-gene signature was constructed and verified. MK-2206 and MK-803 were utilized to block the RTK pathway and mevalonate pathway induced abnormal metabolism. Energy metabolism in GBM with activated EGFR pathway was monitored. The antitumor effect of Osimertinib and Atorvastatin assisted by temozolomide (TMZ) was analyzed by an intracranial tumor model in vivo. RESULTS: GBM with high EGFR expression had characteristics of lipid remodeling and maintaining high cholesterol levels, supported by the single-cell RNA sequencing and metabolomics of clinical GBM samples. Inhibition of the EGFR/AKT and mevalonate pathways could remodel energy metabolism by repressing the tricarboxylic acid cycle and modulating ATP production. Mechanistically, the EGFR/AKT pathway upregulated the expressions of acyl-CoA synthetase short-chain family member 3 (ACSS3), acyl-CoA synthetase long-chain family member 3 (ACSL3), and long-chain fatty acid elongation-related gene ELOVL fatty acid elongase 2 (ELOVL2) in an NF-κB-dependent manner. Moreover, inhibition of the mevalonate pathway reduced the EGFR level on the cell membranes, thereby affecting the signal transduction of the EGFR/AKT pathway. Therefore, targeting the EGFR/AKT and mevalonate pathways enhanced the antitumor effect of TMZ in GBM cells and animal models. CONCLUSIONS: Our findings not only uncovered the mechanism of metabolic reprogramming in EGFR-activated GBM but also provided a combinatorial therapeutic strategy for clinical GBM management.
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Glioblastoma , Animales , Línea Celular Tumoral , Metabolismo Energético , Receptores ErbB/genética , Receptores ErbB/metabolismo , Ácidos Grasos , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Ligasas/metabolismo , Ácido Mevalónico/antagonistas & inhibidores , Ácido Mevalónico/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Temozolomida/farmacología , Temozolomida/uso terapéuticoRESUMEN
N6-Isopentenyladenosine (i6A) is a naturally occurring modified nucleoside displaying in vitro and in vivo antiproliferative and pro-apoptotic properties. In our previous studies, including an in silico inverse virtual screening, NMR experiments and in vitro enzymatic assays, we demonstrated that i6A targeted farnesyl pyrophosphate synthase (FPPS), a key enzyme involved in the mevalonate (MVA) pathway and prenylation of downstream proteins, which are aberrant in several cancers. Following our interest in the anticancer effects of FPPS inhibition, we developed a panel of i6A derivatives bearing bulky aromatic moieties in the N6 position of adenosine. With the aim of clarifying molecular action of N6-benzyladenosine analogs on the FPPS enzyme inhibition and cellular toxicity and proliferation, herein we report the evaluation of the N6-benzyladenosine derivatives' (compounds 2a-m) effects on cell viability and proliferation on HCT116, DLD-1 (human) and MC38 (murine) colorectal cancer cells (CRC). We found that compounds 2, 2a and 2c showed a persistent antiproliferative effect on human CRC lines and compound 2f exerted a significant effect in impairing the prenylation of RAS and Rap-1A proteins, confirming that the antitumor activity of 2f was related to the ability to inhibit FPPS activity.
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Adenosina/química , Antineoplásicos/química , Neoplasias Colorrectales/tratamiento farmacológico , Geraniltranstransferasa/genética , Adenosina/análogos & derivados , Adenosina/farmacología , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Neoplasias Colorrectales/genética , Simulación por Computador , Ensayos de Selección de Medicamentos Antitumorales , Geraniltranstransferasa/antagonistas & inhibidores , Células HCT116 , Humanos , Ácido Mevalónico/antagonistas & inhibidores , Ácido Mevalónico/metabolismo , Ácido Mevalónico/farmacología , Ratones , Relación Estructura-Actividad , Interfaz Usuario-ComputadorRESUMEN
Despite encouraging progresses achieved in the management of viral diseases, efficient strategies to counteract infections are still required. The current global challenge highlighted the need to develop a rapid and cost-effective strategy to counteract the SARS-CoV-2 pandemic. Lipid metabolism plays a crucial role in viral infections. Viruses can use the host lipid machinery to support their life cycle and to impair the host immune response. The altered expression of mevalonate pathway-related genes, induced by several viruses, assures survival and spread in host tissue. In some infections, statins, HMG-CoA-reductase inhibitors, reduce cholesterol in the plasma membrane of permissive cells resulting in lower viral titers and failure to internalize the virus. Statins can also counteract viral infections through their immunomodulatory, anti-inflammatory and anti-thrombotic effects. Beyond statins, interfering with the mevalonate pathway could have an adjuvant effect in therapies aimed at mitigating endothelial dysfunction and deregulated inflammation in viral infection. In this review we depicted the historical and current evidence highlighting how lipid homeostasis and mevalonate pathway targeting represents a valid approach to rapidly neutralize viruses, focusing our attention to their potential use as effective targets to hinder SARS-CoV-2 morbidity and mortality. Pros and cons of statins and Mevalonate-pathway inhibitors have been also dissected.
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COVID-19/metabolismo , Homeostasis , Metabolismo de los Lípidos , Ácido Mevalónico/metabolismo , COVID-19/virología , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hipolipemiantes/farmacología , Hipolipemiantes/uso terapéutico , Ácido Mevalónico/antagonistas & inhibidores , SARS-CoV-2/aislamiento & purificación , Tratamiento Farmacológico de COVID-19RESUMEN
BACKGROUND: Ovarian cancer remains the most fatal gynecological malignancy. Current therapeutic options are limited due to late diagnosis in the majority of the cases, metastatic spread to the peritoneal cavity and the onset of chemo-resistance. Thus, novel therapeutic approaches are required. Statins and amino-bisphosphonates are inhibitors of the mevalonate pathway, which is a fundamental pathway of cellular metabolism, essential for cholesterol production and posttranslational protein farnesylation and geranylgeranylation. While this pathway has emerged as a promising treatment target in several human malignancies, its potential as a therapeutic approach in ovarian cancer is still not fully understood. METHODS: Human ovarian cancer cell lines (IGROV-1, A2780, A2780cis) were treated with increasing concentrations (0.5-100 µM) of statins (simvastatin, atorvastatin, rosuvastatin) and zoledronic acid. Effects on cell vitality and apoptosis were assessed using Cell Titer Blue®, Caspase 3/7 Glo®, clonogenic assays as well as cleaved poly (ADP-ribose) polymerase (cPARP) detection. The inhibition of the mevalonate pathway was confirmed using Western Blot of unprenylated Ras and Rap1a proteins. Quantitative real-time PCR and ELISA were used to analyze modulations on several key regulators of ovarian cancer tumorigenesis. RESULTS: The treatment of IGROV-1 and A2780 cells with statins and zoledronic acid reduced vitality (by up to 80%; p < 0.001) and induced apoptosis by up to 8-folds (p < 0.001) in a dose-dependent fashion. Rescue experiments using farnesyl pyrophosphate or geranylgeranyl pyrophosphate evidenced that blocked geranylgeranylation is the major underlying mechanism of the pro-apoptotic effects. Gene expression of the tumor-promoting cytokines and mediators, such as transforming growth factor (TGF)-ß1, vascular endothelial growth factor (VEGF), interleukin (IL)-8, and IL-6 were significantly suppressed by statins and zoledronic acid by up to 90% (p < 0.001). For all readouts, simvastatin was most potent of all agents used. Cisplatin-resistant A2780cis cells showed a relative resistance to statins and zoledronic acid. However, similar to the effects in A2780 cells, simvastatin and zoledronic acid significantly induced caspase 3/7 activation (6-folds; p < 0.001). CONCLUSION: Our in vitro findings point to promising anti-tumor effects of statins and zoledronic acid in ovarian cancer and warrant additional validation in preclinical and clinical settings.
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Supervivencia Celular/efectos de los fármacos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Ácido Mevalónico/antagonistas & inhibidores , Neoplasias Ováricas/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Atorvastatina/farmacología , Línea Celular Tumoral , Resistencia a Antineoplásicos , Femenino , Expresión Génica/efectos de los fármacos , Humanos , Interleucina-6/genética , Interleucina-8/efectos de los fármacos , Interleucina-8/genética , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Fosfatos de Poliisoprenilo/farmacología , Prenilación/efectos de los fármacos , Rosuvastatina Cálcica/farmacología , Sesquiterpenos/farmacología , Simvastatina/farmacología , Factor de Crecimiento Transformador beta1/efectos de los fármacos , Factor de Crecimiento Transformador beta1/genética , Factor A de Crecimiento Endotelial Vascular/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/genética , Ácido Zoledrónico/farmacologíaRESUMEN
Oncolytic virus is an attractive anticancer agent that selectively lyses cancer through targeting cancer cells rather than normal cells. Although M1 virus is effective against several cancer types, certain cancer cells present low sensitivity to it. Here we identified that most of the components in the cholesterol biosynthesis pathway are downregulated after M1 virus infection. Further functional studies illustrate that mevalonate/protein farnesylation/ras homolog family member Q (RHOQ) axis inhibits M1 virus replication. Further transcriptome analysis shows that RHOQ knockdown obviously suppresses Rab GTPase and ATP-mediated membrane transporter system, which may mediate the antiviral effect of RHOQ. Based on this, inhibition of the above pathway significantly enhances the anticancer potency of M1 virus in vitro, in vivo, and ex vivo. Our research provides an intriguing strategy for the rational combination of M1 virus with farnesyl transferase inhibitors to enhance therapeutic efficacy.
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Colesterol/química , Ácido Mevalónico/antagonistas & inhibidores , Ácido Mevalónico/metabolismo , Viroterapia Oncolítica , Virus Oncolíticos/fisiología , Replicación Viral , Animales , Línea Celular Tumoral , Supervivencia Celular , Regulación hacia Abajo , Farnesiltransferasa/antagonistas & inhibidores , Femenino , Técnicas de Silenciamiento del Gen , Células HCT116 , Humanos , Ratones , Ratones Endogámicos BALB C , Trasplante de Neoplasias , Prenilación de Proteína , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Proteínas de Unión al GTP rab/metabolismoRESUMEN
INTRODUCTION: Statins are a class of drugs, which act by inhibiting the rate-limiting enzyme of cholesterol biosynthesis (3-hydroxy-3-methyl-glutaryl-CoA reductase). The inhibition of mevalonate synthesis leads to subsequent inhibition of downstream products of this pathway, which explains the pleiotropic effects of these agents in addition to their well-known lipid-lowering effects. Accumulating evidence suggests that statins might be beneficial in various obstetric and gynecologic conditions. METHODS: Literature searches were performed in PubMed and EMBASE for articles with content related to statins in obstetrics and gynecology. The findings are hereby reviewed and discussed. RESULTS: Inhibition of mevalonate pathway leads to subsequent inhibition of downstream products such as geranyl pyrophosphate, farnesyl pyrophosphate, and geranylgeranyl pyrophosphate. These products are required for proper intracellular localization of several proteins, which play important roles in signaling pathways by regulating membrane trafficking, motility, proliferation, differentiation, and cytoskeletal organization. The pleiotropic effects of statins can be summarized in 4 categories: antiproliferative, anti-invasive, anti-inflammatory, and antiangiogenic. The growing body of evidence is promising for these agents to be beneficial in endometriosis, polycystic ovary syndrome, adhesion prevention, ovarian cancer, preeclampsia, and antiphospholipid syndrome. Although in vivo studies showed varying degrees of benefit on fibroids and preterm birth, appropriately designed clinical trials are needed to make definitive conclusions. CONCLUSION: Statins might play a role in the treatment of endometriosis, polycystic ovary syndrome, adhesion prevention, ovarian cancer, preeclampsia, and antiphospholipid syndrome.
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Enfermedades Urogenitales Femeninas/tratamiento farmacológico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Femenino , Enfermedades Urogenitales Femeninas/metabolismo , Ginecología , Humanos , Ácido Mevalónico/antagonistas & inhibidores , Ácido Mevalónico/metabolismo , Obstetricia , Transducción de Señal , Resultado del TratamientoRESUMEN
BACKGROUND: Modifications of lipid metabolism have been progressively accepted as a hallmark of tumor cells and in particular, an elevated lipogenesis has been described in various types of cancers. OBJECTIVE: Important or deregulated activity of the mevalonate pathway has been demonstrated in different tumors and a wide range of studies have suggested that tumor cells are more dependent on the unceasing availability of mevalonate pathway metabolites than their non-malignant complements. METHODS: This study provides an overview of the state of the art of statins treatment on human cancer. RESULTS: In recent times, various actions have been proposed for statins in different physiological and pathological conditions beyond anti-inflammation and neuroprotection activity. Statins have been shown to act through mevalonate-dependent and -independent mechanisms able to affect several tissue functions and modulating specific signal transduction pathways that could account for statin pleiotropic effect. Based on their characteristics, statins represent ideal candidates for repositioning in cancer therapy. CONCLUSION: In this review article, we provide an overview of the current preclinical and clinical status of statins as antitumor agents. In addition, we evaluated various patents that describe the role of mevalonate pathway inhibitors and methods to determine if cancer cells are sensitive to statins treatment.
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Antineoplásicos/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Reposicionamiento de Medicamentos/métodos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Ácido Mevalónico/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Animales , Antineoplásicos/química , Antineoplásicos/metabolismo , Sistemas de Liberación de Medicamentos/tendencias , Reposicionamiento de Medicamentos/tendencias , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/química , Inhibidores de Hidroximetilglutaril-CoA Reductasas/metabolismo , Ácido Mevalónico/metabolismo , Neoplasias/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiologíaRESUMEN
Only 40% of patients with advanced ovarian cancer survive more than 5 years. We have previously shown that pitavastatin induces regression of ovarian cancer xenografts in mice. To evaluate whether the response of ovarian cancer cells to pitavastatin is potentiated by farnesyl diphosphate synthase inhibitors or geranylgeraniol transferase I inhibitors, we evaluated combinations of pitavastatin with zoledronic acid, risedronate and GGTI-2133 in a panel of ovarian cancer cells. Pitavastatin (IC50 = 0.6-14 µM), zoledronic acid (IC50 = 21-57 µM), risedronate (IC50 > 100 µM) or GGTI-2133 (IC50 > 25 µM) inhibited the growth of ovarian cancer cell cultures. Combinations of pitavastatin with zoledronic acid displayed additive or synergistic effects in cell growth assays in 10 of 11 cell lines evaluated as well as in trypan blue exclusion, cellular ATP or caspase 3/7, 8 and 9 assays. Pitavastatin reduced levels of GGT-IIß and the membrane localization of several small GTPases and this was potentiated by zoledronic acid. siRNA to GGT-Iß and GGT-IIß used in combination, but not when used individually, significantly increased the sensitivity of cells to pitavastatin. These data suggest that zoledronic acid, a drug already in clinical use, may be usefully combined with pitavastatin in the treatment of ovarian cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Ácido Mevalónico/antagonistas & inhibidores , Neoplasias Ováricas/tratamiento farmacológico , Línea Celular Tumoral , Diterpenos/antagonistas & inhibidores , Femenino , GTP Fosfohidrolasas/metabolismo , Geraniltranstransferasa/antagonistas & inhibidores , Humanos , Imidazoles/administración & dosificación , Leucina/administración & dosificación , Leucina/análogos & derivados , Naftalenos/administración & dosificación , Neoplasias Ováricas/metabolismo , Quinolinas/administración & dosificación , Ácido Zoledrónico/administración & dosificaciónRESUMEN
PURPOSE: Mevalonate pathway inhibitors are potentially useful chemotherapeutic agents showing growth inhibition and pro-apoptotic effects in cancer cells. The effects of statins and bisphosphonates on cancer growth are attributed to a reduction in protein isoprenylation. Post-translational modification and activation of GTPase binding Ras superfamily permit the recruitment of these signal proteins to membranes where they mediate the cancer phenotype. Here, the effects of three inhibitors of the mevalonate pathway and one specific inhibitor of sterol regulatory element-binding proteins were studied in both an ER-negative, Ras-inactive breast (MDA-MB-231) and lung adenocarcinoma (CaLu-1) cells in vitro. METHODS: Treated cells were subject to genome-wide gene expression profiling. A gene subset was established so that the epithelial to mesenchymal transition (EMT) could be observed and compared with signalling protein shifts. RESULTS: Within the subset, some genes normally up-regulated during EMT were asymmetrically reduced by a Δ-24 DHCR inhibitor in the lung cells. Signalling proteins associated with caveolae were down-regulated by this oxidoreductase inhibitor, while those associated with membrane rafts were up-regulated. CONCLUSIONS: This study decouples isoprenylation effects from cholesterol events per se. The data support a hypothesis that caveolae are abolished by Δ-24 DHCR intervention and it is revealed that these microdomains are vital EMT signalling structures for lung cells but not ER- and Ras-negative breast cells. When signalling by extracellular signals is quenched by removal of the hydrophilic conduit provided by caveolae, the transcriptome responds by moving the cellular identity towards quiescence.
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Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/secundario , Antineoplásicos/uso terapéutico , Caveolas/efectos de los fármacos , Inhibidores Enzimáticos/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Ácido Mevalónico/antagonistas & inhibidores , Adenocarcinoma/metabolismo , Adenocarcinoma del Pulmón , Antineoplásicos/farmacología , Caveolas/fisiología , Caveolina 1/genética , Caveolina 1/metabolismo , Línea Celular Tumoral , Inhibidores Enzimáticos/farmacología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundario , Metástasis de la Neoplasia , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/antagonistas & inhibidores , Fenotipo , Proadifeno/farmacología , Proadifeno/uso terapéuticoRESUMEN
In response to carbohydrate deprivation or prolonged fasting the ketone bodies, ß-hydroxybutyrate (ßHB) and acetoacetate (AcAc), are produced from the incomplete ß-oxidation of fatty acids in the liver. Neither ßHB nor AcAc are well utilized for synthesis of sterols or fatty acids in human or rat liver. To study the effects of ketones on cholesterol homeostasis a novel ßHB ester (KE) ((R)-3-hydroxybutyl (R)-3-hydroxybutyrate) was synthesized and given orally to rats and humans as a partial dietary carbohydrate replacement. Rats maintained on a diet containing 30-energy % as KE with a concomitant reduction in carbohydrate had lower plasma cholesterol and mevalonate (-40 and -27 %, respectively) and in the liver had lower levels of the mevalonate precursors acetoacetyl-CoA and HMG-CoA (-33 and -54 %) compared to controls. Whole liver and membrane LDL-R as well as SREBP-2 protein levels were higher (+24, +67, and +91 %, respectively). When formulated into a beverage for human consumption subjects consuming a KE drink (30-energy %) had elevated plasma ßHB which correlated with decreased mevalonate, a liver cholesterol synthesis biomarker. Partial replacement of dietary carbohydrate with KE induced ketosis and altered cholesterol homeostasis in rats. In healthy individuals an elevated plasma ßHB correlated with lower plasma mevalonate.
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Ácido 3-Hidroxibutírico/agonistas , Anticolesterolemiantes/administración & dosificación , Colesterol/sangre , Suplementos Dietéticos , Hidroxibutiratos/administración & dosificación , Ácido Mevalónico/antagonistas & inhibidores , Ácido 3-Hidroxibutírico/sangre , Ácido 3-Hidroxibutírico/metabolismo , Acilcoenzima A/antagonistas & inhibidores , Acilcoenzima A/metabolismo , Adulto , Animales , Anticolesterolemiantes/metabolismo , Bebidas , Biomarcadores/sangre , Biomarcadores/química , Biomarcadores/metabolismo , Desayuno , Membrana Celular/metabolismo , Colesterol/metabolismo , Femenino , Humanos , Hidroxibutiratos/metabolismo , Hígado/metabolismo , Masculino , Ácido Mevalónico/sangre , Ácido Mevalónico/metabolismo , Ratas Sprague-Dawley , Receptores de LDL/agonistas , Receptores de LDL/metabolismo , Proteína 2 de Unión a Elementos Reguladores de Esteroles/agonistas , Proteína 2 de Unión a Elementos Reguladores de Esteroles/metabolismo , Adulto JovenRESUMEN
The Wnt-inhibitor dickkopf-1 (DKK-1) promotes cancer-induced osteolytic bone lesions by direct inhibition of osteoblast differentiation and indirect activation of osteoclasts. DKK-1 is highly expressed in human breast cancer cells and can be suppressed by inhibitors of the mevalonate pathway such as statins and amino-bisphosphonates. However, supraphysiological concentrations are required to suppress DKK-1. We show that a sequential mevalonate pathway blockade using statins and amino-bisphosphonates suppresses DKK-1 more significantly than the individual agents alone. Thus, the reduction of the DKK-1 expression and secretion in the human osteotropic tumor cell lines MDA-MB-231, MDA-MET, and MDA-BONE by zoledronic acid was potentiated by the combination with low concentrations of statins (atorvastatin, simvastatin, and rosuvastatin) by up to 75% (p < 0.05). The specific rescue of prenylation using farnesyl pyrophosphate or geranylgeranyl pyrophosphate revealed that these effects were mediated by suppressed geranylgeranylation rather than by suppressed farnesylation. Moreover, combining low concentrations of statins (1 µM atorvastatin or 0.25 µM simvastatin) and zoledronic acid at low concentrations resulted in an at least 50% reversal of breast cancer-derived DKK-1-mediated inhibition of osteogenic markers in C2C12 cells (p < 0.05). Finally, the intratumoral injection of atorvastatin and zoledronic acid in as subcutaneous MDA-MB-231 mouse model reduced the serum level of human DKK-1 by 25% compared to untreated mice. Hence our study reveals that a sequential mevalonate pathway blockade allows for the combined use of low concentration of statins and amino-bisphosphonates. This combination still significantly suppresses breast cancer-derived DKK-1 to levels where it can no longer inhibit Wnt-mediated osteoblast differentiation.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Ácido Mevalónico/metabolismo , Animales , Atorvastatina/administración & dosificación , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral/efectos de los fármacos , Difosfonatos/administración & dosificación , Relación Dosis-Respuesta a Droga , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Imidazoles/administración & dosificación , Péptidos y Proteínas de Señalización Intercelular/genética , Ácido Mevalónico/antagonistas & inhibidores , Ratones Desnudos , Osteoblastos/efectos de los fármacos , Osteoblastos/metabolismo , Rosuvastatina Cálcica/administración & dosificación , Simvastatina/administración & dosificación , Ensayos Antitumor por Modelo de Xenoinjerto , Ácido ZoledrónicoRESUMEN
PURPOSE: We investigated the synergistic effect of simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor plus radiation therapy, on the proliferation and survival of gastric cancer (GC) and colorectal cancer (CRC) cells. We also studied several genes involved in the simvastatin/radiation-induced effects. METHODS AND MATERIALS: Gastric cancer (AGS, SNU601, MKN1, and MKN28) and CRC (CoLo320, SW48, HT29, and HCT8) cell lines were treated with 0.2 µM simvastatin alone, or in combination with 0 to 4 Gy of radiation, and subjected to clonogenic survival and proliferation assays in vitro. To assess the molecular mechanism of the combination treatment, we performed microarray analysis, immunoblot assays, small interfering RNA knockdown experiments, and plasmid rescue assays. The antitumoral effects of simvastatin and radiation were evaluated in vivo using xenograft models. RESULTS: The combination therapy of simvastatin plus radiation inhibited basal clonogenic survival and proliferation of GC and CRC cells in vitro. Simvastatin suppressed the expression of BIRC5 and CTGF genes in these cancer cells. In vivo, the combined treatment with simvastatin and radiation significantly reduced the growth of xenograft tumors compared with treatment with radiation alone. CONCLUSION: We suggest that simvastatin has a synergistic effect with radiation on GC and CRC through the induction of apoptosis, which may be mediated by a simultaneous inhibition of BIRC5 and CTGF expression. A clinical trial of simvastatin in combination with radiation in patients with GC or CRC is warranted.
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Quimioradioterapia/métodos , Neoplasias Colorrectales/terapia , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Simvastatina/uso terapéutico , Neoplasias Gástricas/terapia , Animales , Apoptosis , Ciclo Celular , Línea Celular Tumoral , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Terapia Combinada/métodos , Factor de Crecimiento del Tejido Conjuntivo/genética , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Femenino , Fluorouracilo/uso terapéutico , Técnicas de Silenciamiento del Gen , Humanos , Proteínas Inhibidoras de la Apoptosis/genética , Proteínas Inhibidoras de la Apoptosis/metabolismo , Ácido Mevalónico/antagonistas & inhibidores , Ratones Endogámicos BALB C , Análisis por Micromatrices/métodos , ARN Interferente Pequeño , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Survivin , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
PURPOSE: Statins are among the most frequently prescribed drugs because of their efficacy and low toxicity in treating hypercholesterolemia. Recently, statins have been reported to inhibit the proliferative activity of cancer cells, especially those with TP53 mutations. Because TP53 mutations occur in almost all ovarian high-grade serous carcinoma (HGSC), we determined whether statins suppressed tumor growth in animal models of ovarian cancer. EXPERIMENTAL DESIGN: Two ovarian cancer mouse models were used. The first one was a genetically engineered model, mogp-TAg, in which the promoter of oviduct glycoprotein-1 was used to drive the expression of SV40 T-antigen in gynecologic tissues. These mice spontaneously developed serous tubal intraepithelial carcinomas (STICs), which are known as ovarian cancer precursor lesions. The second model was a xenograft tumor model in which human ovarian cancer cells were inoculated into immunocompromised mice. Mice in both models were treated with lovastatin, and effects on tumor growth were monitored. The molecular mechanisms underlying the antitumor effects of lovastatin were also investigated. RESULTS: Lovastatin significantly reduced the development of STICs in mogp-TAg mice and inhibited ovarian tumor growth in the mouse xenograft model. Knockdown of prenylation enzymes in the mevalonate pathway recapitulated the lovastatin-induced antiproliferative phenotype. Transcriptome analysis indicated that lovastatin affected the expression of genes associated with DNA replication, Rho/PLC signaling, glycolysis, and cholesterol biosynthesis pathways, suggesting that statins have pleiotropic effects on tumor cells. CONCLUSIONS: The above results suggest that repurposing statin drugs for ovarian cancer may provide a promising strategy to prevent and manage this devastating disease.
Asunto(s)
Antineoplásicos/farmacología , Carcinoma in Situ/tratamiento farmacológico , Ácido Mevalónico/antagonistas & inhibidores , Neoplasias Ováricas/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Animales , Carcinoma in Situ/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Replicación del ADN/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Humanos , Lovastatina/farmacología , Ratones , Neoplasias Ováricas/metabolismo , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
The mevalonate pathway provides metabolites for post-translational modifications such as farnesylation, which are critical for the activity of RAS downstream signaling. Subsequently occurring regulatory processes can induce an aberrant stimulation of DNA methyltransferase (DNMT1) as well as changes in histone deacetylases (HDACs) and microRNAs in many cancer cell lines. Inhibitors of the mevalonate pathway are increasingly recognized as anticancer drugs. Extensive evidence indicates an intense cross-talk between signaling pathways, which affect growth, differentiation, and apoptosis either directly or indirectly via epigenetic mechanisms. Herein, we show data obtained by novel transcriptomic and corresponding methylomic or proteomic analyses from cell lines treated with pharmacologic doses of respective inhibitors (i.e., simvastatin, ibandronate). Metabolic pathways and their epigenetic consequences appear to be affected by a changed concentration of NADPH. Moreover, since the mevalonate metabolism is part of a signaling network, including vitamin D metabolism or fatty acid synthesis, the epigenetic activity of associated pathways is also presented. This emphasizes the far-reaching epigenetic impact of metabolic therapies on cancer cells and provides some explanation for clinical observations, which indicate the anticancer activity of statins and bisphosphonates.
Asunto(s)
Antineoplásicos/farmacología , ADN (Citosina-5-)-Metiltransferasas/biosíntesis , Epigénesis Genética/efectos de los fármacos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Ácido Mevalónico/antagonistas & inhibidores , Neoplasias/genética , Línea Celular Tumoral , ADN (Citosina-5-)-Metiltransferasa 1 , Difosfonatos/farmacología , Regulación hacia Abajo , Ácidos Grasos/biosíntesis , Femenino , Humanos , Hidroximetilglutaril-CoA-Reductasas NADP-Dependientes/metabolismo , Ácido Ibandrónico , Lovastatina/farmacología , Ácido Mevalónico/metabolismo , MicroARNs/genética , NADP/metabolismo , Neoplasias/metabolismo , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Simvastatina/farmacología , Vitamina D/metabolismoRESUMEN
The cerebellum is an important locus for motor learning and higher cognitive functions, and Purkinje cells constitute a key component of its circuit. Biochemically, significant turnover of cholesterol occurs in Purkinje cells, causing the activation of the mevalonate pathway. The mevalonate pathway has important roles in cell survival and development. In this study, we investigated the outcomes of mevalonate inhibition in immature and mature mouse cerebellar Purkinje cells in culture. Specifically, we found that the inhibition of the mevalonate pathway by mevastatin resulted in cell death, and geranylgeranylpyrophosphate (GGPP) supplementation significantly enhanced neuronal survival. The surviving immature Purkinje cells, however, exhibited dendritic developmental deficits. The morphology of mature cells was not affected. The inhibition of squalene synthase by zaragozic acid caused impaired dendritic development, similar to that seen in the GGPP-rescued Purkinje cells. Our results indicate GGPP is required for cell survival and squalene synthase for the cell development of Purkinje cells. Abnormalities in Purkinje cells are linked to motor-behavioral learning disorders such as cerebellar ataxia. Thus, serious caution should be taken when using drugs that inhibit geranylgeranylation or the squalene-cholesterol branch of the pathway in the developing stage.
Asunto(s)
Diferenciación Celular/fisiología , Ácido Mevalónico/antagonistas & inhibidores , Ácido Mevalónico/farmacología , Células de Purkinje/fisiología , Transducción de Señal/fisiología , Animales , Diferenciación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Células Cultivadas , Femenino , Lovastatina/análogos & derivados , Lovastatina/farmacología , Ratones , Embarazo , Células de Purkinje/efectos de los fármacos , Transducción de Señal/efectos de los fármacosRESUMEN
Statins are well known competitive inhibitors of hydroxymethylglutaryl-CoA reductase enzyme (HMG-CoA reductase), thus traditionally used as cholesterol-lowering agents. In recent years, more and more effects of statins have been revealed. Nowadays alterations of lipid metabolism have been increasingly recognized as a hallmark of cancer cells. Consequently, much attention has been directed toward the potential of statins as therapeutic agents in the oncological field. Accumulated in vitro and in vivo clinical evidence point out the role of statins in a variety of human malignancies, in regulating tumor cell growth and anti-tumor immune response. Herein, we summarize and discuss, in light of the most recent observations, the anti-tumor effects of statins, underpinning the detailed mode of action and looking for their true significance in cancer prevention and treatment, to determine if and in which case statin repositioning could be really justified for neoplastic diseases.
Asunto(s)
Antineoplásicos/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Neoplasias/tratamiento farmacológico , Animales , Antineoplásicos/farmacología , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Ácido Mevalónico/antagonistas & inhibidores , Ácido Mevalónico/metabolismo , Neoplasias/metabolismo , Neoplasias/prevención & controlRESUMEN
Geraniol (G)-a natural compound present in the essential oils of many aromatic plants-has attracted interest for its potential antitumor effects. The molecular mechanisms of the growth inhibition and apoptosis induced by G in cancer cells, however, remain unclear. In this study, we investigated the effects of G on cell proliferation in culture in A549 cells and in vivo in those same tumor cells implanted in nude mice fed diets supplemented with 25, 50, and 75 mmol G/kg. We demonstrated that G caused a dose- and time-dependent growth inhibition of A549 cells and tumor growth in vivo along with an induction of apoptosis. Moreover, further in vivo assays indicated that G decreased the levels of 3-hydroxymethylglutarylcoenzyme-A reductase-the rate-limiting enzyme in cholesterogenesis-in a dose-dependent manner along with cholesterogenesis and cholesterolemia in addition to reducing the amount of membrane-bound Ras protein. These results showed that the doses of G used in this work, though nontoxic to animals, clearly inhibited the mevalonate pathway, which is closely linked to cell proliferation and increased apoptosis in A549 tumors, but not in normal mouse-liver cells. Accordingly, we suggest that G displays significant antitumor activity and should be a promising candidate for cancer chemotherapy.
Asunto(s)
Antineoplásicos/farmacología , Ácido Mevalónico/metabolismo , Terpenos/farmacología , Monoterpenos Acíclicos , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/prevención & control , Adenocarcinoma del Pulmón , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Colesterol/sangre , Femenino , Humanos , Hidroximetilglutaril-CoA Reductasas/genética , Hidroximetilglutaril-CoA Reductasas/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/prevención & control , Ácido Mevalónico/antagonistas & inhibidores , Ratones , Ratones Desnudos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The clinical benefits of statins are strongly related to their low density lipoprotein cholesterol (LDL-C) lowering properties. However, considering that the pharmacological target of statins, the 3-hydroxy-3-methyl-3-glutaryl coenzyme A (HMG-CoA) reductase, is one of the upstream enzyme of the mevalonate pathway, its inhibition may determine a substantial impoverishment of additional lipid moieties required for a proper cellular function. From this hypothesis, several experimental and clinical evidences have been reported indicating additional effects of statins beyond the LDL-C lowering, in particular anti-inflammatory and immunomodulatory effects. Thus statin therapy, indicated for hyperlipidemic patients for primary and secondary prevention of coronary heart disease (CHD) has begun to be considered effective in other diseases not necessarily linked to altered lipid profile. In the present review we summarized the current clinical evidence of the efficacy and safety profile of statins in a variety of diseases, such as rheumatoid arthritis, venous thromboembolism, liver diseases, polycystic ovary syndrome, and age-related macular degeneration. As discussed in the review, pending large, well designed, randomized trials, it is reasonable to conclude that there is no definitive evidence for the use of statins in the aforementioned diseases.
Asunto(s)
Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Animales , Artritis Reumatoide/tratamiento farmacológico , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Hepatopatías/tratamiento farmacológico , Degeneración Macular/tratamiento farmacológico , Ácido Mevalónico/antagonistas & inhibidores , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Tromboembolia Venosa/tratamiento farmacológicoRESUMEN
Virtually any cell type in a mammalian organism uses Acetyl CoA to yield mevalonate, through the activity of the 3-hydroxy-3-methyl-glutaryl-CoA reductase enzyme and, ultimately, cholesterol. Statins have long and quite successfully been used as cholesterol lowering drugs. They reversibly inhibit the 3-hydroxy-3-methyl-glutaryl-CoA reductase activity, which is rate limiting in the early steps of the cholesterol synthesis pathway. In addition to these effects, it has also been amply shown that statins may efficiently trigger cancer cell apoptosis, making them a plausible therapeutic option for the treatment of cancer. Whether statins may prevent cancer occurrence is a matter of debate and an unanswered question; undoubtedly experimental models have clearly demonstrated the potential of statins as direct cytotoxic agents, which can reduce tumour development or metastasis spread, even more so when combined with cytotoxic drugs. Until now, however, only few data in humans support the idea that statins could rightfully belong to the group of anticancer drugs. Nevertheless, as cancer cell metabolism is being thoroughly revisited, the mevalonate pathway has recently been reported as truly oncogenic, presenting the attractive possibility that mevalonate pathway inhibitors, such as statins, may join the ranks of anticancer drugs.
Asunto(s)
Neoplasias Colorrectales/tratamiento farmacológico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Colorrectales/prevención & control , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Ácido Mevalónico/antagonistas & inhibidores , Ácido Mevalónico/metabolismoRESUMEN
Osteoclastogenesis and osteoblastogenesis, the balancing acts for optimal bone health, are under the regulation of small guanosine triphosphate-binding proteins (GTPases) including Ras, Rac, Rho and Rab. The activities of GTPases require post-translational modification with mevalonate-derived prenyl pyrophosphates. Mevalonate deprivation induced by competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase (e.g., statins) prevents the activation of GTPases, suppresses the expression of the receptor for activation of nuclear factor kappa B (NFκB) ligand (RANKL) and activation of NFκB and, consequently, inhibits osteoclast differentiation and induces osteoclast apoptosis. In contrast, statin-mediated inactivation of GTPases enhances alkaline phosphatase activity and the expression of bone morphogenetic protein-2, vascular epithelial growth factor, and osteocalcin in osteoblasts and induces osteoblast proliferation and differentiation. Animal studies show that statins inhibit bone resorption and increase bone formation. The anabolic effect of statins and other mevalonate pathway-suppressive pharmaceuticals resembles the anti-osteoclastogenic and bone-protective activities conferred by dietary isoprenoids, secondary products of plant mevalonate metabolism. The tocotrienols, vitamin E molecules with HMG CoA reductase-suppressive activity, induce mevalonate deprivation and concomitantly suppress the expression of RANKL and cyclooxygenase-2, the production of prostaglandin E2 and the activation of NFκB. Accordingly, tocotrienols inhibit osteoclast differentiation and induce osteoclast apoptosis, impacts reminiscent of those of statins. In vivo studies confirm the bone protective activity of tocotrienols at nontoxic doses. Blends of tocotrienols, statins and isoprenoids widely found in fruits, vegetables, grains, herbs, spices, and essential oils may synergistically suppress osteoclastogenesis while promoting osteoblastogenesis, offering a novel approach to bone health that warrants clinical studies.