RESUMEN
Metabolic endotoxemia is a severe health problem for residents in developed countries who follow a Western diet, disrupting intestinal microbiota and the whole organism's homeostasis. Although the effect of endotoxin on the human immune system is well known, its long-term impact on the human body, lasting many months or even years, is unknown. This is due to the difficulty of conducting in vitro and in vivo studies on the prolonged effect of endotoxin on the central nervous system. In this article, based on the available literature, we traced the path of endotoxin from the intestines to the blood through the intestinal epithelium and factors promoting the development of metabolic endotoxemia. The presence of endotoxin in the bloodstream and the inflammation it induces may contribute to lowering the blood-brain barrier, potentially allowing its penetration into the central nervous system; although, the theory is still controversial. Microglia, guarding the central nervous system, are the first line of defense and respond to endotoxin with activation, which may contribute to the development of neurodegenerative diseases. We traced the pro-inflammatory role of endotoxin in neurodegenerative diseases and its impact on the epigenetic regulation of microglial phenotypes.
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Endotoxemia , Endotoxinas , Microbioma Gastrointestinal , Enfermedades Neurodegenerativas , Endotoxemia/metabolismo , Endotoxemia/etiología , Humanos , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/etiología , Animales , Endotoxinas/metabolismo , Microglía/metabolismo , Microglía/patología , Barrera Hematoencefálica/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Mucosa Intestinal/microbiología , Inflamación/metabolismoRESUMEN
Madhuca longifolia is an evergreen tree distributed in India, Nepal, and Sri Lanka. This tree is commonly known as Mahua and is used in traditional medicine. It was demonstrated that ethanol extract from the bark of M. longifolia possessed potent cytotoxic activity towards two melanoma cell lines, in contrast to aqueous extract that exhibited no activity. Apart from being selectively cytotoxic to cancer cells (with no activity towards non-cancerous fibroblasts), the studied extract induced apoptosis and increased reactive oxygen species generation in melanoma cells. Additionally, the use of the extract together with dacarbazine (both in non-toxic concentrations) resulted in the enhancement of their anticancer activity. Moreover, the pretreatment of melanoma cells with M. longifolia extract potentiated the activity of a low dose of dacarbazine to an even higher extent. It was concluded that ethanol extract of M. longifolia sensitized human melanoma cells to chemotherapeutic drugs. It can therefore be interesting as a promising source of compounds for prospective combination therapy.
Asunto(s)
Apoptosis , Dacarbazina , Sinergismo Farmacológico , Etanol , Melanoma , Corteza de la Planta , Extractos Vegetales , Especies Reactivas de Oxígeno , Humanos , Extractos Vegetales/farmacología , Extractos Vegetales/química , Corteza de la Planta/química , Melanoma/tratamiento farmacológico , Melanoma/metabolismo , Melanoma/patología , Línea Celular Tumoral , Dacarbazina/farmacología , Apoptosis/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Etanol/química , Supervivencia Celular/efectos de los fármacos , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/químicaRESUMEN
Naringenin is a flavonoid found in many fruits and herbs, most notably in grapefruits. In recent years, this compound and its derivatives have been of great interest due to their high biological activity, including fungicidal and bactericidal effects, also in relation to multidrug-resistant bacteria. Membrane interactions of naringenin oxime (NO) and its 7-O-alkyl (7-alkoxy) derivatives, such as methyl (7MENO), ethyl (7ETNO), isopropyl (7IPNO), n-butyl (7BUNO) and n-pentyl (7PENO) were studied. Thermotropic properties of model membranes were investigated via differential scanning calorimetry (DSC), the influence on lipid raft mimicking giant unilamellar vesicles (GUVs) via fluorescence microscopy, and membrane permeability via measuring calcein leakage from liposomes. Molecular calculations supplemented the study. The influence of naringenin oximes on two strains of multidrug resistant bacteria: Staphylococcus aureus KJ and Enterococcus faecalis 37VRE was also investigated. In DSC studies all compounds reduced the temperature and enthalpy of main phase transition and caused disappearing of the pretransition. NO was the least active. The reduction in the area of surface domains in GUVs was observed for NO. Compounds NO and 7BUNO resulted in very low secretion of calcein from liposomes (permeabilityâ¯<â¯3â¯%). The highest results were observed for 7MENO (88.4â¯%) and 7IPNO (78.5â¯%). When bacterial membrane permeability was investigated all compounds caused significant release of propidium iodide from S. aureus (31.6-87.0â¯% for concentration 128⯵g/mL). In the case of E. faecalis, 7ETNO (75.7â¯%) and NO (28.8â¯%) were the most active. The rest of the tested compounds showed less activity (permeabilityâ¯<â¯13.9â¯%). The strong evidence was observed that antibacterial activity of the tested compounds may be associated with their interaction with bacterial membrane.
Asunto(s)
Membrana Celular , Flavanonas , Oximas , Staphylococcus aureus , Flavanonas/farmacología , Flavanonas/química , Oximas/farmacología , Oximas/química , Staphylococcus aureus/efectos de los fármacos , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Enterococcus faecalis/efectos de los fármacos , Antibacterianos/farmacología , Antibacterianos/química , Liposomas Unilamelares/metabolismo , Liposomas Unilamelares/química , Rastreo Diferencial de Calorimetría , Permeabilidad de la Membrana Celular/efectos de los fármacos , Pruebas de Sensibilidad MicrobianaRESUMEN
Chalcones are naturally produced by many plants, and constitute precursors for the synthesis of flavons and flavanons. They were shown to possess antibacterial, antifungal, anti-cancer, and anti- inflammatory properties. The goal of the study was to assess the suitability of three synthetic methoxychalcones as potential anticancer agents. In a panel of colon cancer cell lines they were demonstrated to be cytotoxic, proapoptotic, causing cell cycle arrest, and increasing intracellular level of reactive oxygen species. Anticancer activity of the compounds was not diminished in the presence of stool extract containing microbial enzymes that could change the structure of chalcones. Moreover, methoxychalcones interacted strongly with model phosphatidylcholine membranes as detected by differential scanning calorimetry. Metohoxychalcones particularly affected the properties of lipid domains in giant unilamellar liposomes formed from raft-mimicking lipid composition. This may be of importance since many molecular targets for therapy of metastatic colon cancer are raft-associated receptors (e.g., receptor tyrosine kinases). The importance of membrane perturbing potency of methoxychalcones for their biological activity was additionally corroborated by the results obtained by molecular modelling.
Asunto(s)
Antineoplásicos , Chalconas , Neoplasias del Colon , Humanos , Chalconas/farmacología , Chalconas/química , Línea Celular , Fosfatidilcolinas , Antineoplásicos/química , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patologíaRESUMEN
Metabolic endotoxemia (ME) is characterized by a 2-3-fold increase in blood endotoxin levels and low-grade systemic inflammation without apparent infection. ME is usually accompanied by metabolic syndrome, characterized by central obesity and hyperlipidemia. According to numerous studies, ME may lead to functional brain disorders, including cognitive decline, depression, and dementia. In the current in vitro study, we aimed to determine the direct and indirect impact of endotoxin (LPS) and palmitic acid (PA), representing saturated fatty acids, on the inflammatory and oxidative stress response in the human microglial HMC3 cells unstimulated and stimulated with IFNγ. The study's results revealed that direct HMC3 cell exposition to endotoxin and PA increased inflammatory response measured as levels of IL-6 and MCP-1 released into the medium and PGE2 levels in cell lysates. Moreover, direct HMC3 cell treatment with PA and LPS induced oxidative stress, i.e., ROS and COX-2 production and lipid peroxidation. On the contrary, an indirect effect of LPS and PA on microglial cells, assessed as the impact of macrophage metabolites, was much lower regarding the inflammatory response, although still associated with oxidative stress. Interestingly, IFNγ had a protective effect on microglial cells, reducing the production of pro-inflammatory mediators and oxidative stress in HMC3 cells treated directly and indirectly with LPS and PA.
Asunto(s)
Endotoxemia , Microglía , Humanos , Ácido Palmítico/farmacología , Ácido Palmítico/metabolismo , Endotoxemia/metabolismo , Lipopolisacáridos/farmacología , Inflamación/metabolismoRESUMEN
Introduction: Metabolic endotoxemia most often results from obesity and is accompanied by an increase in the permeability of the intestinal epithelial barrier, allowing co-absorption of bacterial metabolites and diet-derived fatty acids into the bloodstream. A high-fat diet (HFD) leading to obesity is a significant extrinsic factor in developing vascular atherosclerosis. In this study, we evaluated the effects of palmitic acid (PA) as a representative of long-chain saturated fatty acids (LCSFA) commonly present in HFDs, along with endotoxin (LPS; lipopolysaccharide) and uremic toxin indoxyl sulfate (IS), on human vascular endothelial cells (HUVECs). Methods: HUVECs viability was measured based on tetrazolium salt metabolism, and cell morphology was assessed with fluorescein-phalloidin staining of cells' actin cytoskeleton. The effects of simultaneous treatment of endothelial cells with PA, LPS, and IS on nitro-oxidative stress in vascular cells were evaluated quantitatively with fluorescent probes. The expression of vascular cell adhesion molecule VCAM-1, E-selectin, and occludin, an essential tight junction protein, in HUVECs treated with these metabolites was evaluated in Western blot. Results: PA, combined with LPS and IS, did not influence HUVECs viability but induced stress on actin fibers and focal adhesion complexes. Moreover, PA combined with LPS significantly enhanced reactive oxygen species (ROS) production in HUVECs but decreased nitric oxide (NO) generation. PA also considerably increased the expression of VCAM-1 and E-selectin in HUVECs treated with LPS or IS but decreased occludin expression. Conclusion: Palmitic acid enhances the toxic effect of metabolic endotoxemia on the vascular endothelium.
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Endotoxemia , Ácido Palmítico , Humanos , Ácido Palmítico/toxicidad , Ácido Palmítico/metabolismo , Selectina E , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Ocludina/metabolismo , Ocludina/farmacología , Lipopolisacáridos/metabolismo , Lipopolisacáridos/farmacología , Molécula 1 de Adhesión Celular Vascular/metabolismo , Molécula 1 de Adhesión Celular Vascular/farmacología , Endotoxemia/metabolismo , Obesidad , Endotelio VascularRESUMEN
Cholesterol is an important component of mammalian cell membranes affecting their fluidity and permeability. Together with sphingomyelin, cholesterol forms microdomains, called lipid rafts. They play important role in signal transduction forming platforms for interaction of signal proteins. Altered levels of cholesterol are known to be strongly associated with the development of various pathologies (e.g., cancer, atherosclerosis and cardiovascular diseases). In the present work, the group of compounds that share the property of affecting cellular homeostasis of cholesterol was studied. It contained antipsychotic and antidepressant drugs, as well as the inhibitors of cholesterol biosynthesis, simvastatin, betulin, and its derivatives. All compounds were demonstrated to be cytotoxic to colon cancer cells but not to non-cancerous cells. Moreover, the most active compounds decreased the level of free cellular cholesterol. The interaction of drugs with raft-mimicking model membranes was visualized. All compounds reduced the size of lipid domains, however, only some affected their number and shape. Membrane interactions of betulin and its novel derivatives were characterized in detail. Molecular modeling indicated that high dipole moment and significant lipophilicity were characteristic for the most potent antiproliferative agents. The importance of membrane interactions of cholesterol homeostasis-affecting compounds, especially betulin derivatives, for their anticancer potency was suggested.
Asunto(s)
Colesterol , Mamíferos , Animales , Membrana Celular/metabolismo , Membranas/metabolismo , Colesterol/metabolismo , HomeostasisRESUMEN
Pectin constitutes an essential component of dietary fiber. Modified pectins from various sources possess potent anticancer and immunomodulatory activities. In this study, two pectins isolated from apple pomace by Trichoderma enzyme treatment, PX (with endo-xylanase) and PCX (with both endo-cellulase and endo-xylanase), were studied in colon cancer cell lines (HCT 116, Caco-2, and HT-29). Both pectins reduced colon cancer cell viability, induced apoptosis, and increased intracellular amounts of reactive oxygen species. Additionally, synergy between pectin and an active form of irinotecan, SN-38, in all aspects mentioned above, was discovered. This drug is a common component of cytotoxic combinations recommended as treatment for colon cancer patients. PX and PCX demonstrated significant anti-inflammatory activity in lipopolysaccharide-stimulated cells. Interaction of apple pectins with galectin-3 and Toll-like Receptor 4 (TLR4) was suggested to be responsible for their anticancer and anti-inflammatory effect. Since PCX was more active than PX in almost all experiments, the role of the enzyme used to obtain the pectin for its biological activity was discussed. It was concluded that co-operation between both enzymes was needed to obtain the molecule of the most beneficial properties. The low molecular mass of PCX together with a high proportion of rhamnogalacturonan I (RG I) regions seemed to be crucial for its superior activity.
RESUMEN
Voltage-gated potassium channels of the Kv1.3 type are considered a potential new molecular target in several pathologies, including some cancer disorders and COVID-19. Lipophilic non-toxic organic inhibitors of Kv1.3 channels, such as statins and flavonoids, may have clinical applications in supporting the therapy of some cancer diseases, such as breast, pancreas, and lung cancer; melanoma; or chronic lymphocytic leukemia. This study focuses on the influence of the co-application of statins-simvastatin (SIM) or mevastatin (MEV)-with flavonoids 8-prenylnaringenin (8-PN), 6-prenylnarigenin (6-PN), xanthohumol (XANT), acacetin (ACAC), or chrysin on the activity of Kv1.3 channels, viability, and the apoptosis of cancer cells in the human T cell line Jurkat. We showed that the inhibitory effect of co-application of the statins with flavonoids was significantly more potent than the effects exerted by each compound applied alone. Combinations of simvastatin with chrysin, as well as mevastatin with 8-prenylnaringenin, seem to be the most promising. We also found that these results correlate with an increased ability of the statin-flavonoid combination to reduce viability and induce apoptosis in cancer cells compared to single compounds. Our findings suggest that the co-application of statins and flavonoids at low concentrations may increase the effectiveness and safety of cancer therapy. Thus, the simultaneous application of statins and flavonoids may be a new and promising anticancer strategy.
Asunto(s)
COVID-19 , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Neoplasias , Apoptosis , Línea Celular , Flavonoides/farmacología , Flavonoides/uso terapéutico , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Canal de Potasio Kv1.3/metabolismo , Neoplasias/tratamiento farmacológico , Simvastatina/farmacologíaRESUMEN
Phenothiazines are known as synthetic antipsychotic drugs that exhibit a wide range of biological effects. Their properties result from the structure and variability of substituents in the heterocyclic system. It is known that different quantum chemical properties have a significant impact on drug behavior in the biological systems. Thus, due to the diversity in the chemical structure of phenothiazines as well as other drugs containing heterocyclic systems, quantum chemical calculations provide valuable methods in predicting their activity. In our study, DFT computations were applied to show some thermochemical parameters (bond dissociation enthalpy-BDE, ionization potential-IP, proton dissociation enthalpy-PDE, proton affinity-PA, and electrontransfer enthalpy-ETE) describing the process of releasing the hydrogen/proton from the hydroxyl group in the side chain of four 2-(trifluoromethyl)phenothiazine (TFMP) derivatives and fluphenazine (FLU). Additional theoretical analysis was carried out based on QTAIM theory. The results allowed theoretical determination of the ability of compounds to scavenge free radicals. In addition, the intramolecular hydrogen bond (H-bond) between the H-atom of the hydroxyl group and the N-atom located in the side chain of the investigated compounds has been identified and characterized.
RESUMEN
Phenolic acids possess many beneficial biological activities, including antioxidant and anti-inflammatory properties. Unfortunately, their low bioavailability restricts their potential medical uses, as it limits the concentration of phenolic acids achievable in the organism. The conjugation with phospholipids constitutes one of the most effective strategies to enhance compounds bioavailability in biological systems. In the present study, the conjugates of anisic (ANISA) and veratric acid (VA) with phosphatidylcholine (PC) were investigated. Since both ANISA and VA are inhibitors of tyrosinase, a melanocyte enzyme, the expression of which increases during tumorigenesis, anticancer potential of the conjugates was tested in several metastatic melanoma cell lines. The conjugates proved to be antiproliferative, apoptosis-inducing and cell-cycle-affecting agents, selective for cancerous cells and not affecting normal fibroblasts. The conjugates substituted by ANISA and VA, respectively, at both the sn-1 and sn-2 positions of PC, appeared the most promising, since they were effective against the vast majority of metastatic melanoma cell lines. Additionally, the conjugation of phenolic acids to PC increased their antioxidant activity. Molecular modeling was employed for the first time to estimate the features of the investigated conjugates relevant to their anticancer properties and membrane permeation. Again, the conjugates substituted by phenolic acid at both the sn-1 and sn-2 positions of PC seemed to be presumably most bioavailable.
Asunto(s)
Antineoplásicos/farmacología , Hidroxibenzoatos/farmacología , Melanoma/tratamiento farmacológico , Metástasis de la Neoplasia/tratamiento farmacológico , Fosfolípidos/farmacología , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Células CACO-2 , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Simulación por Computador , Fibroblastos/efectos de los fármacos , Humanos , Fosfatidilcolinas/farmacología , Ácido Vanílico/análogos & derivados , Ácido Vanílico/farmacologíaRESUMEN
Isobavachalcone (IBC) is an active substance from the medicinal plant Psoralea corylifolia. This prenylated chalcone was reported to possess antioxidative, anti-inflammatory, antibacterial, and anticancer activities. Multidrug resistance (MDR) associated with the over-expression of the transporters of vast substrate specificity such as ABCB1 (P-glycoprotein) belongs to the main causes of cancer chemotherapy failure. The cytotoxic, MDR reversing, and ABCB1-inhibiting potency of isobavachalcone was studied in two cellular models: human colorectal adenocarcinoma HT29 cell line and its resistant counterpart HT29/Dx in which doxorubicin resistance was induced by prolonged drug treatment, and the variant of MDCK cells transfected with the human gene encoding ABCB1. Because MDR modulators are frequently membrane-active substances, the interaction of isobavachalcone with model phosphatidylcholine bilayers was studied by means of differential scanning calorimetry. Molecular modeling was employed to characterize the process of membrane permeation by isobavachalcone. IBC interacted with ABCB1 transporter, being a substrate and/or competitive inhibitor of ABCB1. Moreover, IBC intercalated into model membranes, significantly affecting the parameters of their main phospholipid phase transition. It was concluded that isobavachalcone interfered both with the lipid phase of cellular membrane and with ABCB1 transporter, and for this reason, its activity in MDR cancer cells was presumptively beneficial.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Chalconas/farmacología , Doxorrubicina/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Psoralea/química , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Animales , Antibióticos Antineoplásicos/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Unión Competitiva , Línea Celular Tumoral , Chalconas/química , Chalconas/aislamiento & purificación , Perros , Combinación de Medicamentos , Resistencia a Antineoplásicos/genética , Expresión Génica , Células HT29 , Humanos , Concentración 50 Inhibidora , Membrana Dobles de Lípidos/química , Membrana Dobles de Lípidos/metabolismo , Células de Riñón Canino Madin Darby , Membranas Artificiales , Modelos Moleculares , Fosfatidilcolinas/química , Fosfatidilcolinas/metabolismo , Extractos Vegetales/química , Plantas Medicinales , Unión Proteica , Transgenes , Verapamilo/farmacologíaRESUMEN
Colorectal cancer (CRC) is the second cause of cancer death worldwide. The composition and enzymatic activity of colonic microbiota can significantly affect the effectiveness of CRC chemotherapy. Irinotecan is a drug widely used to treat colon cancer. However, the transformation of a drug-glucuronide (SN-38G) back to its active form (SN-38) by bacterial ß-glucuronidase (GUS) constitutes the primary reason for the observed intestinal toxicity of irinotecan. It was demonstrated that novel enzymatically extracted apple pectin (PC) might be a promising candidate for an adjunct to irinotecan therapy. PC itself reduced the viability of HCT 116 and Caco-2 colorectal cancer cells, induced apoptosis, and increased intracellular reactive oxygen species production. Moreover, PC enhanced the cytotoxic and proapoptotic effect of irinotecan (at concentrations below its IC50), i.e., synergistic effect was recorded. Additionally, PC exhibited potent anti-inflammatory properties and prevented adhesion of prototype adherent-invasive E. coli (AIEC) LF82 strain and laboratory K-12C600 strain to colon cancer cells. PC was also identified to be an effective inhibitor of bacterial GUS activity. Altogether, novel apple pectin was identified as a promising candidate for a supplement to irinotecan therapy that might alleviate its side-effects via inhibition of bacterial GUS and thus increasing its therapeutic efficacy.
RESUMEN
Terpenes constitute one of the largest groups of natural products. They exhibit a wide range of biological activities including antioxidant, anticancer, and drug resistance modulating properties. Saffron extract and its terpene constituents have been demonstrated to be cytotoxic against various types of cancer cells, including breast, liver, lung, pancreatic, and colorectal cancer. In the present work, we have studied anticancer properties of TMPE, a newly synthesized monoterpene derivative of ß-cyclocitral-the main volatile produced by the stigmas of unripe crocuses. TMPE presented selective cytotoxic activity to doxorubicin-resistant colon cancer cells and was identified to be an effective MDR modulator in doxorubicin-resistant cancer cells. Synergy between this derivative and doxorubicin was observed. Most probably, TMPE inhibited transport activity of ABCB1 protein without affecting its expression level. Analysis of TMPE physicochemical parameters suggested it was not likely to be transported by ABCB1. Molecular modeling showed TMPE being more reactive molecule than the parental compound-ß-cyclocitral. Analysis of electrostatic potential maps of both compounds prompted us to hypothesize that reduced reactivity as well as susceptibility to electrophilic attack were related to the lower general toxicity of ß-cyclocitral. All of the above pointed to TMPE as an interesting candidate molecule for MDR reversal in cancer cells.
Asunto(s)
Antineoplásicos , Neoplasias del Colon/metabolismo , Crocus/química , Ciclohexenos/química , Resistencia a Antineoplásicos , Compuestos Orgánicos , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/química , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Aldehídos/química , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Sitios de Unión , Proliferación Celular/efectos de los fármacos , Ciclohexenos/farmacología , Diterpenos/química , Células HT29 , Humanos , Compuestos Orgánicos/síntesis química , Compuestos Orgánicos/farmacología , Unión ProteicaRESUMEN
Multidrug resistance (MDR) that occurs in cancer cells constitutes one of the major reasons for chemotherapy failure. The main molecular mechanism of MDR is overexpression of protein transporters from the ATP-binding cassette (ABC) superfamily, such as ABCB1 (multidrug resistance protein 1 (MDR1), P-glycoprotein). At the expense of ATP hydrolysis, ABCB1 pumps a diverse range of substrates (including anticancer drugs) out of the cell, thereby reducing their intracellular concentration. In the present study, the ability of two patented disiloxanes (SILA-409 and SILA-421) to reverse drug resistance in human colon adenocarcinoma cell lines LoVo and LoVo/Dx was investigated. It was demonstrated that both compounds in concentrations of 0.5-1 µM strongly increased the sensitivity of LoVo/Dx cells to doxorubicin. By means of an accumulation test in which rhodamine 123 was used as an ABCB1 substrate analogue, both organosilicon compounds were also shown to inhibit ABCB1 transport activity. The intracellular accumulation of doxorubicin was also increased, and more drug entered the cellular nuclei of resistant cells in the presence of the studied compounds. In conclusion, both SILA-409 and SILA-421 were demonstrated to be effective MDR reversal agents in resistant human colon cancer cells.
Asunto(s)
Neoplasias del Colon/metabolismo , Doxorrubicina/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Piperazinas/farmacología , Siloxanos/farmacología , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Sinergismo Farmacológico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , HumanosRESUMEN
Voltage-gated potassium channel Kv1.3 is an integral membrane protein, which is selectively permeable for potassium ions and is activated upon a change of membrane potential. Channel activation enables transportation of potassium ions down their electrochemical gradient. Kv1.3 channel is expressed in many cell types, both normal and cancer. Activity of the channel plays an important role in cell proliferation and apoptosis. Inhibition of Kv1.3 channel may be beneficial in therapy of several diseases including some cancer disorders. This review focuses on Kv1.3 channel as a new potentially attractive molecular target in cancer therapy. In the first part, changes in the channel expression in selected cancer disorders are described. Then, the role of the channel activity in cancer cell proliferation and apoptosis is presented. Finally, it is shown that some low molecular weight organic inhibitors of the channel including selected biologically active plant-derived polycyclic compounds may selectively induce apoptosis of Kv1.3-expressing cancer cells while sparing normal cells and healthy organs. These compounds may be promising candidates for putative application in therapy of some cancer disorders, such as melanoma, pancreatic ductal adenocarcinoma (PDAC), or B-type chronic lymphocytic leukemia (B-CLL).
RESUMEN
Since none of the multidrug resistance (MDR) modulators tested so far found their way into clinic, a novel approach to overcome the MDR of cancer cells has been proposed. The combined use of two MDR modulators of dissimilar mechanisms of action was suggested to benefit from the synergy between them. The effect of three phenothiazine derivatives that were used as single agents and in combination with simvastatin on cell growth, apoptosis induction, activity, and expression of cyclooxygenase-2 (COX-2) in doxorubicin-resistant colon cancer cells (LoVo/Dx) was investigated. Treatment of LoVo/Dx cells by phenothiazine derivatives combined with simvastatin resulted in an increase of doxorubicin cytotoxicity and its intracellular accumulation as compared to the treatment with phenothiazine derivatives that were used as single agents. Similarly, LoVo/Dx cells treated with two-component mixture of modulators showed the reduced expression of ABCB1 (P-glycoprotein) transporter and COX-2 enzyme, both on mRNA and protein level. Reduced expression of anti-apoptotic Bcl-2 protein and increased expression of pro-apoptotic Bax were also detected. Additionally, COX-2 activity was diminished, and caspase-3 activity was increased to a higher extent by phenothiazine derivative:simvastatin mixtures than by phenothiazine derivatives themselves. Therefore, the introduction of simvastatin strengthened the anti-MDR, anti-inflammatory, and pro-apoptotic properties of phenothiazines in LoVo/Dx cells.
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Apoptosis/efectos de los fármacos , Neoplasias del Colon/enzimología , Neoplasias del Colon/patología , Ciclooxigenasa 2/metabolismo , Doxorrubicina/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Fenotiazinas/farmacología , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Caspasa 3/metabolismo , Línea Celular Tumoral , Doxorrubicina/química , Sinergismo Farmacológico , Humanos , Fenotiazinas/química , Simvastatina/química , Simvastatina/farmacología , Proteína X Asociada a bcl-2/metabolismoRESUMEN
BACKGROUND: Incidence of cancer is still increasing. Chemotherapy is often unsuccessful; moreover, anticancer drugs cause serious side-effects. It is necessary to develop effective agents for combination therapies that would increase antitumor effects of treatment and reduce its side-effects. MATERIALS AND METHODS: Anticancer activity of oxicam derivatives (PR17 and PR18) alone and in combination with simvastatin on doxorubicin-resistant colon cancer cells was studied. Apoptosis was investigated via caspase-3 activation assay as well as via western blot analysis of expression of apoptotic components, B-cell lymphoma 2 protein (BCL2) and BCL2-associated X protein (BAX). Expression and activity of cyclo-oxygenase-2 (COX2) was also assessed. RESULTS: Oxicam derivatives induced apoptosis through a caspase-3-dependent pathway, up-regulated BAX expression, and down-regulated BCL2 expression. Additionally, oxicam derivatives reduced expression and activity of COX2. Effect of oxicam derivatives on these processes was strongly potentiated by simvastatin. CONCLUSION: Oxicam derivatives at low concentrations effectively inhibit growth of cancer cells after co-administration with simvastatin.
Asunto(s)
Apoptosis , Neoplasias del Colon/patología , Óxidos S-Cíclicos/farmacología , Doxorrubicina/farmacología , Resistencia a Antineoplásicos , Simvastatina/farmacología , Tiazinas/farmacología , Antineoplásicos/farmacología , Caspasa 3/metabolismo , Línea Celular Tumoral , Supervivencia Celular , Óxidos S-Cíclicos/química , Ciclooxigenasa 2/metabolismo , Sinergismo Farmacológico , Activación Enzimática , Humanos , Concentración 50 Inhibidora , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Tiazinas/química , Regulación hacia Arriba , Proteína X Asociada a bcl-2/metabolismoRESUMEN
The idea of the use of anticancer drugs together with a chemosensitizer emerged as the strategy of reversal of multidrug resistance (MDR) of cancer cells expressing ABC proteins many years ago. The approaches relying on the use of a single chemosensitizer have never resulted in a clinical success. Therefore, the application of drug combinations of two or more compounds with different mechanisms of action might be an alternative approach to increase the success rate. In the present study the cytotoxic and NF-κB inhibition potential of the phenothiazine derivative, MAE-TPR, was evaluated. MAE-TPR was demonstrated to be an effective doxorubicin-resistance modulator in human adenocarcinoma cell line LoVo/Dx. In the presence of MAE-TPR cytotoxicity of doxorubicin was elevated, and its intracellular accumulation increased. Strong synergism occurred between MAE-TPR and Dox. MAE-TPR diminished also the expression of ABCB1 transporter (P-glycoprotein) by affecting NF-κB pathway. Theobromine, a phytochemical from cocoa, which was barely active itself, strongly augmented MDR reversal potency of MAE-TPR. The effect of the combination of phenothiazine derivative with theobromine on cancer cells was studied for the first time in the present work. It was concluded that the use of the proposed combination of two modulators might be a promising strategy for MDR reversal since modulators could be used in concentrations much lower than in case of their single application and in that way the risk of intolerable side-effects could be reduced.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Cacao/química , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Fenotiazinas/química , Fenotiazinas/farmacología , Teobromina/farmacología , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Línea Celular Tumoral , Doxorrubicina/química , Doxorrubicina/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Sinergismo Farmacológico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Modelos Moleculares , Conformación Molecular , FN-kappa B/metabolismo , Teobromina/químicaRESUMEN
The resistance of cancer cells to a variety of structurally non-related cytotoxic drugs is known as multidrug resistance phenomenon (MDR). In cellular membranes an activity of MDR transporters such as P-glycoprotein (ABCB1) is affected by their lipid environment. Many various compounds have been examined for their ability to restore drug-sensitivity of resistant cancer cells. Statins, inhibitors of the key enzyme of mevalonate pathway HMG-CoA (3-hydroxy-3-methyl-glutaryl-coenzyme A) reductase are drugs commonly prescribed in order to reduce serum level of cholesterol and to diminish the risk of cardiovascular disease. Statins as drugs that influence lipid composition of cell membrane and in that way they also exert influence on lipid bilayer properties appear to be good candidates as MDR modulators. In this work it was shown that statins - mevastatin and simvastatin exert antiproliferative, pro-apoptotic and reversing drug resistance effect in human colon adenocarcinoma cell line LoVo and its drug-resistant subline LoVo/Dx. A hypothesis was also checked whether flavones, which as it is well known are able to influence the biosynthesis of cholesterol, may change the anticancer activity of statins. Our investigations have revealed that combined use of statins and studied flavonoids results in enhanced cell growth inhibition and apoptosis and lower cancer cell proliferation as compared to the application only statins alone. Moreover, in drug resistant LoVo/Dx cells a stronger decrease of resistance to doxorubicine was observed in the presence of statins in combination with flavones as compared to the effect observed for statins only.