RESUMO
Euphorbia seguieriana ssp. seguieriana Necker (ES) and Euphorbia cyparissias (EC) with a habitat in the Deliblato Sands were the subject of this examination. The latexes of these so far insufficiently investigated species of the Euphorbia genus are used in traditional medicine for the treatment of wounds and warts on the skin. To determine their chemical composition, non-targeted screening of the latexes' chloroform extracts was performed using liquid chromatography coupled with quadrupole time-of-flight mass spectrometry employing an electrospray ionization source (LC-ESI QTOF MS). The analysis of the obtained results showed that the latexes of ES and EC represent rich sources of diterpenes, tentatively identified as jatrophanes, ingenanes, tiglianes, myrsinanes, premyrsinanes, and others. Examination of the anticancer activity of the ES and EC latex extracts showed that both extracts significantly inhibited the growth of the non-small cell lung carcinoma NCI-H460 and glioblastoma U87 cell lines as well as of their corresponding multi-drug resistant (MDR) cell lines, NCI-H460/R and U87-TxR. The obtained results also revealed that the ES and EC extracts inhibited the function of P-glycoprotein (P-gp) in MDR cancer cells, whose overexpression is one of the main mechanisms underlying MDR.
RESUMO
Most of the currently available cytotoxic agents for tackling cancer are devoid of selectivity, thus causing severe side-effects. This situation stimulated us to develop new antiproliferative agents with enhanced affinity towards tumour cells. We focused our attention on novel chalcogen-containing compounds (thiosemicarbazones, disulfides, selenoureas, thio- and selenocyanates), and particularly on selenium derivatives, as it has been documented that this kind of compounds might act as prodrugs releasing selenium-based reactive species on tumour cells. Particularly interesting in terms of potency and selectivity was a pharmacophore comprised by a selenocyanato-alkyl fragment connected to a p-phenylenediamine residue, where the nature of the second amino moiety (free, Boc-protected, enamine-protected) provided a wide variety of antiproliferative activities, ranging from the low micromolar to the nanomolar values. The optimized structure was in turn conjugated through a peptide linkage with biotin (vitamin B7), a cellular growth promoter, whose receptor is overexpressed in numerous cancer cells; the purpose was to develop a selective vector towards malignant cells. Such biotinylated derivative behaved as a very strong antiproliferative agent, achieving GI50 values in the low nM range for most of the tested cancer cells; moreover, it was featured with an outstanding selectivity, with GI50 > 100 µM against human fibroblasts. Mechanistic studies on the mode of inhibition of the biotinylated selenocyanate revealed (Annexin-V assay) a remarkable increase in the number of apoptotic cells compared to the control experiment; moreover, depolarization of the mitochondrial membrane was detected by flow cytometry analysis, and with fluorescent microscopy, what supports the apoptotic cell death. Prior to the apoptotic events, cytostatic effects were observed against SW1573 cells using label-free cell-living imaging; therefore, tumour cell division was prevented. Multidrug resistant cell lines exhibited a reduced sensitivity towards the biotinylated selenocyanate, probably due to its P-gp-mediated efflux. Remarkably, antiproliferative levels could be restored by co-administration with tariquidar, a P-gp inhibitor; this approach can, therefore, overcome multidrug resistance mediated by the P-gp efflux system.
Assuntos
Antineoplásicos , Citostáticos , Selênio , Humanos , Citostáticos/farmacologia , Linhagem Celular Tumoral , Selênio/farmacologia , Cianatos/farmacologia , Apoptose , Proliferação de Células , Antineoplásicos/farmacologia , Antineoplásicos/química , Relação Estrutura-AtividadeRESUMO
The Plectranthus genus is commonly used in traditional medicine due to its potential to treat several illnesses, including bacterial infections and cancer. As such, aiming to screen the antibacterial and cytotoxic activities of extracts, sixteen selected Plectranthus species with medicinal potential were studied. In total, 31 extracts obtained from 16 Plectranthus spp. were tested for their antibacterial and anticancer properties. Well diffusion method was used for preliminary antibacterial screening. The minimum inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) values of the five most active acetonic extracts (P. aliciae, P. japonicus, P. madagascariensis var. "Lynne", P. stylesii, and P. strigosus) were determined. After preliminary toxicity evaluation on Artemia salina L., their cytotoxic properties were assessed on three human cancer cell lines (HCT116, MCF-7, and H460). These were also selected for mechanism of resistance studies (on NCI-H460/R and DLD1-TxR cells). An identified compound-parvifloron D-was tested in a pair of sensitive and MDR-Multidrug resistance cancer cells (NCI-H460 and NCI-H460/R) and in normal bronchial fibroblasts MRC-5. The chemical composition of the most active extract was studied through high performance liquid chromatography with a diode array detector (HPLC-DAD/UV) and liquid chromatography-mass spectrometry (LC-MS). Overall, P. strigosus acetonic extract showed the strongest antimicrobial and cytotoxic potential that could be explained by the presence of parvifloron D, a highly cytotoxic diterpene. This study provides valuable information on the use of the Plectranthus genus as a source of bioactive compounds, namely P. strigosus with the potential active ingredient the parvifloron D.
Assuntos
Abietanos/farmacologia , Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antinematódeos/farmacologia , Extratos Vegetais/farmacologia , Plectranthus/química , Abietanos/química , Abietanos/isolamento & purificação , Animais , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antifúngicos/química , Antifúngicos/isolamento & purificação , Antinematódeos/química , Antinematódeos/isolamento & purificação , Artemia/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Enterococcus faecalis/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Células HCT116 , Humanos , Células MCF-7 , Testes de Sensibilidade Microbiana , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Pseudomonas aeruginosa/efeitos dos fármacos , Saccharomyces cerevisiae/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Teucrum chamaedrys L. is one of the known medicinal plants, useful for treatment of various health problems, especially digestive. In this study, we investigated methanol, ethyl-acetate and acetone extracts of T. chamaedrys in respect to their anticancer properties in SW480 colorectal cancer cells. MATERIALS AND METHODS: Cytotoxicity and proapoptotic potential were assessed by MTT cell viability assay and AO/EB double staining. Molecular mechanisms of induced apoptosis were determined by monitoring Fas receptor protein expression through immunofluorescence, Caspase 8 and 9 activity, as well as concentrations of O2.- spectrophotometrically. Additionally, mRNA expression of biotransformation enzymes (CYP1A1, CYP1B1, GSTP1) and membrane transporters (MRP1 and MRP2) involved in drug resistance were investigated by qPCR method. Qualitative analysis of individual phenolic compounds was performed by reversed phase HPLC-MS analysis. RESULTS: Methanol extract shows the best cytotoxicity and selectivity compared to ethyl-acetate and acetone extracts, mainly causing apoptosis of SW480â¯cells, without affecting normal HaCaT keratinocytes. The increased expression of Fas receptor protein and caspase 8 activity indicate that the death receptor-mediated pathway plays a crucial role in the observed apoptosis. The increased caspase 9 activity and O2.- concentration suggest that mitochondria are also involved in the apoptosis. T. chamaedrys methanol extract inhibits mRNA expression of CYP1A1, CYP1B1, GSTP1, MRP1 and MRP2 in SW480â¯cells. CONCLUSIONS: Induction of apoptosis and inhibition of CYP1A1, CYP1B1, GSTP1, MRP1 and MRP2 mRNA expression implies that T. chamaedrys can serve as a valuable source of bioactive compounds as dietary supplements or selective anticancer agents, with the ability to induce apoptosis and modulate drug resistance in colorectal cancer cells.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Extratos Vegetais/farmacologia , Teucrium , Apoptose/efeitos dos fármacos , Biotransformação/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1B1/genética , Flores , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glutationa S-Transferase pi/genética , Humanos , Proteína 2 Associada à Farmacorresistência Múltipla , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genéticaRESUMO
The main reasons for the inefficiency of standard glioblastoma (GBM) therapy are the occurrence of chemoresistance and the invasion of GBM cells into surrounding brain tissues. New therapeutic approaches obstructing these processes may provide substantial survival improvements. The purpose of this study was to assess the potential of lipophilic antioxidant coenzyme Q10 (CoQ10) as a scavenger of reactive oxygen species (ROS) to increase sensitivity to temozolomide (TMZ) and suppress glioma cell invasion. To that end, we used a previously established TMZ-resistant RC6 rat glioma cell line, characterized by increased production of ROS, altered antioxidative capacity, and high invasion potential. CoQ10 in combination with TMZ exerted a synergistic antiproliferative effect. These results were confirmed in a 3D model of microfluidic devices showing that the CoQ10 and TMZ combination is more cytotoxic to RC6 cells than TMZ monotherapy. In addition, cotreatment with TMZ increased expression of mitochondrial antioxidant enzymes in RC6 cells. The anti-invasive potential of the combined treatment was shown by gelatin degradation, Matrigel invasion, and 3D spheroid invasion assays as well as in animal models. Inhibition of MMP9 gene expression as well as decreased N-cadherin and vimentin protein expression implied that CoQ10 can suppress invasiveness and the epithelial to mesenchymal transition in RC6 cells. Therefore, our data provide evidences in favor of CoQ10 supplementation to standard GBM treatment due to its potential to inhibit GBM invasion through modulation of the antioxidant capacity.
Assuntos
Antioxidantes/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Temozolomida/uso terapêutico , Ubiquinona/análogos & derivados , Animais , Neoplasias Encefálicas/patologia , Resistencia a Medicamentos Antineoplásicos , Glioblastoma/patologia , Humanos , Masculino , Camundongos , Ratos Wistar , Temozolomida/farmacologia , Ubiquinona/farmacologia , Ubiquinona/uso terapêuticoRESUMO
INTRODUCTION AND AIM: Hyperprolactinaemia in pregnancy leads to mild and reversible changes in the maternal skeletal system, and medicamentous hyperprolactinemia causes more detrimental effects. We conducted an experimental study to evaluate differences between Prlr gene expression in the duodenum, vertebrae and kidneys during physiological and medicamentous hyperprolactinaemia, which could influence calcium homeostasis. METHODS: Experimental animals (18 weeks old, Wistar female rats) were divided as follows: group P (nine rats that were 3 weeks pregnant), group M (ten rats that were intramuscularly administrated sulpiride (10 mg/kg) twice daily for 3 weeks), and the control group (C, ten age-matched nulliparous rats, 18-week-old). Laboratory investigations included measurements of serum ionized calcium, phosphorus, urinary calcium and phosphorus excretion, osteocalcin (OC), serum procollagen type 1 N-terminal propeptide (P1NP), vitamin D, parathyroid hormone (PTH) and prolactin (PRL). Relative quantification of gene expression for prolactin receptors in the duodenum, vertebrae and kidneys was determined using real-time PCR. RESULTS: Expression of the Prlr gene was significantly higher in the duodenum (p < 0.001) and lower in vertebrae (p < 0.001) and kidneys (p < 0.01) in rats with physiological hyperprolactinaemia (PHP) than in the control group. Significantly lower Prlr expression in the duodenum was verified (p < 0.001), along with increased Prlr gene expression in vertebrae (p < 0.001) and kidneys (p < 0.01), in rats with medicamentous hyperprolactinaemia (MHP) than in the C group. CONCLUSIONS: Downregulation of Prlr gene expression in the duodenum may explain the diminished intestinal calcium absorption in medicamentous hyperprolactinaemia. Prolactin takes calcium from the skeletal system following increased Prlr gene expression in the vertebrae to maintain calcium homeostasis, which increases the harmful effect on bone metabolism compared to that of physiological hyperprolactinaemia.
Assuntos
Osso e Ossos/metabolismo , Duodeno/metabolismo , Hiperprolactinemia/metabolismo , Rim/metabolismo , Receptores da Prolactina/metabolismo , Animais , Cálcio/sangue , Feminino , Hiperprolactinemia/induzido quimicamente , Osteocalcina/sangue , Hormônio Paratireóideo/sangue , Fósforo/sangue , Gravidez , Ratos , Ratos Wistar , Receptores da Prolactina/genética , SulpiridaRESUMO
AIM: 6,7-dehydroroyleanone (DHR) is a cytotoxic abietane present in the essential oil of Plectranthus madagascariensis. METHODS/RESULTS: Different extraction parameters were tested, and its extraction optimization was accomplished with a Clevenger apparatus-based hydrodistillation. After isolation, its effect on microtubules, P-glycoprotein and caspases was assessed on several cell lines and the compound was coupled with hybrid nanoparticles. The results show that DHR does not interfere with microtubule formation, but evades the resistance mechanisms of P-glycoprotein. Strong activation of caspases-3 and -9 indicates that DHR is able to induce apoptosis by triggering the intrinsic cell death pathway. Moreover, the assembly of DHR with hybrid nanoparticles was able to potentiate the effect of DHR in cancer cells. CONCLUSION: DHR seems to be a promising starting material with anticancer properties to further be explored.
Assuntos
Abietanos/química , Antineoplásicos Fitogênicos/química , Subfamília B de Transportador de Cassetes de Ligação de ATP/química , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Abietanos/isolamento & purificação , Abietanos/farmacologia , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Nanopartículas/química , Óleos Voláteis/química , Extratos Vegetais/química , Plectranthus/química , Plectranthus/metabolismoRESUMO
Medicinal value of natural products comes from symbiotic and competitive evolution in Earth's complex biosphere. Billions of years of co-evolutionary interactions among millions of species have produced a large repertoire of defense molecules effective in fighting bacteria, viral, and fungal pathogens. Each species contains millions of different and useful molecules and new research technologies enabled the screening of molecules and complex mixtures from diverse biological sources. Traditional use of plants and other species led to the discovery of many bioactive compounds with various properties. In the last four decades, a large number of them were evaluated for their potential to treat cancer. Penetration of drugs into the cancer cell is necessary for their lethal pharmacological effect through interaction with intracellular target molecules. Increased activity of membrane efflux pumps reduces the intracellular drug accumulation, thereby preventing drug-target interactions. The discovery of the efflux transporter P-glycoprotein (P-gp) in multidrug resistant (MDR) cancer cells prompted the efforts in overcoming drug resistance by P-gp inhibition. The search for nontoxic anticancer agents from natural sources able to overcome MDR has been imperative in the field of drug design and discovery. Herein, we review various natural compounds from diverse sources emphasizing their potential to inhibit P-gp activity and/or expression.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/farmacologia , Produtos Biológicos/farmacologia , Animais , Desenho de Fármacos , Descoberta de Drogas/métodos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologiaRESUMO
Medicinal plants are recognized from ancient times as a source of diverse therapeutic agents and many of them are used as dietary supplements. Comprehensive approaches are needed that would identify bioactive components with evident activity against specific indications and provide a better link between science (ethno-botany, chemistry, biology and pharmacology) and market. Recently, the bark of black alder (Alnus glutinosa) appeared at market in the form of food supplement for treatment of different skin conditions. This study aimed to evaluate protective effects of two diarylheptanoids isolated from the bark of black alder: platyphylloside, 5(S)-1,7-di(4-hydroxyphenyl)-3-heptanone-5-O-ß-D-glucopyranoside (1) and its newly discovered analog 5(S)-1,7-di(4-hydroxyphenyl)-5-O-ß-D-[6-(E-p-coumaroylglucopyranosyl)]heptane-3-one (2) towards doxorubicin damaging activity. To that end, we employed HaCaT cells, non-cancerous human keratinocytes commonly used for skin regenerative studies. Diarylheptanoids significantly antagonized the effects of doxorubicin by lowering the sensitivity of HaCaT cells to this drug. Compound 2 prevented doxorubicin-induced cell death by activating autophagy. Both 1 and 2 protected HaCaT cells against doxorubicin-induced DNA damage. They significantly promoted migration and affected F-actin distribution. These results indicate that chemo-protective effects of diarylheptanoids may occur at multiple subcellular levels. Therefore, diarylheptanoids 1 and 2 could be considered as protective agents for non-cancerous dividing cells during chemotherapy.
Assuntos
Diarileptanoides/química , Ilex/química , Queratinócitos/efeitos dos fármacos , Casca de Planta/química , Morte Celular/efeitos dos fármacos , Linhagem Celular , Adutos de DNA , Dano ao DNA/efeitos dos fármacos , Diarileptanoides/isolamento & purificação , Doxorrubicina , Glucosídeos/química , Glucosídeos/isolamento & purificação , Humanos , Estrutura Molecular , Substâncias Protetoras/química , Substâncias Protetoras/isolamento & purificaçãoRESUMO
Diarylheptanoids belong to polyphenols, a group of plant secondary metabolites with multiple biological properties. Many of them display antioxidative, cytotoxic, or anticancer actions and are increasingly recognized as potential therapeutic agents. The aim of this study was to evaluate antioxidant and cytoprotective activity of two diarylheptanoids: platyphylloside 5(S)-1,7-di(4-hydroxyphenyl)-3-heptanone-5-O-ß-D-glucopyranoside (1) and its newly discovered analog 5(S)-1,7-di(4-hydroxyphenyl)-5-O-ß-D-[6-(E-p-coumaroylglucopyranosyl)]heptane-3-one (2), both isolated from the bark of black alder (Alnus glutinosa). To that end, we have employed a cancer cell line (NCI-H460), normal human keratinocytes (HaCaT), and peripheral blood mononuclear cells. The effects on cell growth were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide colorimetric assay. Cell death was examined by annexin V/propidium iodide staining on a flow cytometer. Reactive oxygen species production was examined by dihydroethidium staining. Mitochondrial structure and doxorubicin localization were visualized by fluorescent microscopy. Gene expression of manganese superoxide dismutase and hypoxia-inducible factor-1α was determined by reverse transcription polymerase chain reaction. Diarylheptanoids antagonized the effects of either doxorubicin or cisplatin, significantly increasing their IC50 values in normal cells. Diarylheptanoid 1 induced the retention of doxorubicin in cytoplasm and reduced mitochondrial fragmentation associated with doxorubicin application. Diarylheptanoid 2 reduced the reactive oxygen species production induced by cisplatin. Both compounds increased the messenger ribonucleic acid expression of enzymes involved in reactive oxygen species elimination (manganese superoxide dismutase and hypoxia-inducible factor-1α). These results indicate that neutralization of reactive oxygen species is an important mechanism of diarylheptanoid action, although these compounds exert a considerable anticancer effect. Therefore, these compounds may serve as protectors of normal cells during chemotherapy without significantly diminishing the effect of the applied chemotherapeutic.
Assuntos
Alnus/química , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Diarileptanoides/farmacologia , Interações Ervas-Drogas , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/química , Morte Celular/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Diarileptanoides/química , Diarileptanoides/isolamento & purificação , Doxorrubicina/análise , Doxorrubicina/metabolismo , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/ultraestrutura , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Casca de Planta/química , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismoRESUMO
Parthenolide, the main bioactive compound of the medicinal plant feverfew (Tanacetum parthenium), is a promising anti-cancer drug. However, the biosynthetic pathway of parthenolide has not been elucidated yet. Here we report on the isolation and characterization of all the genes from feverfew that are required for the biosynthesis of parthenolide, using a combination of 454 sequencing of a feverfew glandular trichome cDNA library, co-expression analysis and metabolomics. When parthenolide biosynthesis was reconstituted by transient co-expression of all pathway genes in Nicotiana benthamiana, up to 1.4µgg(-1) parthenolide was produced, mostly present as cysteine and glutathione conjugates. These relatively polar conjugates were highly active against colon cancer cells, with only slightly lower activity than free parthenolide. In addition to these biosynthetic genes, another gene encoding a costunolide and parthenolide 3ß-hydroxylase was identified opening up further options to improve the water solubility of parthenolide and therefore its potential as a drug.
Assuntos
Nicotiana , Plantas Geneticamente Modificadas , Sesquiterpenos/metabolismo , Metabolômica/métodos , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Plantas Geneticamente Modificadas/genética , Plantas Geneticamente Modificadas/metabolismo , Tanacetum parthenium/enzimologia , Tanacetum parthenium/genética , Nicotiana/genética , Nicotiana/metabolismoRESUMO
Jatrophane diterpenes were shown to be inhibitors of P-glycoprotein (P-gp). There are also evidences on their microtubule-interacting activity in cancer cells. We evaluated new anti-cancer characteristics of two jatrophane type compounds from Euphorbia dendroides. For that purpose, the model system of sensitive non-small cell lung cancer cell line (NCI-H460) and its resistant counterpart (NCI-H460/R) was used. Although both jatrophanes showed inhibitory effect on cancer cell growth, they were non-toxic for peripheral blood mononuclear cells (PBMC). We examined their effects in combination with paclitaxel (PTX), a well-known mitotic spindle interacting chemotherapeutic. Jatrophanes overcome PTX resistance in concentration-dependent manner in MDR cancer cell line (NCI-H460/R). We observed that this synergistic effect is not caused merely by P-gp inhibition. In combination with PTX, jatrophanes induce cell killing and change cell cycle distribution leading to G2/M arrest. Furthermore, they exert an anti-angiogenic effect by decreasing the vascular endothelial growth factor (VEGF) secretion. The reduction of the level of mdr1 mRNA expression in sensitive cells, suggests that these compounds could not contribute to the development of resistance. In conclusion, present study provides a rational basis for the new cancer treatment approach with jatrophanes that are non-toxic to normal cells and have new favorable anti-cancer characteristics.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Diterpenos/farmacologia , Euphorbia/química , Extratos Vegetais/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Paclitaxel/uso terapêutico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
BACKGROUND/AIM: Insulin glargine is a long-acting insulin analog that mimics normal basal insulin secretion without pronounced peaks. The aim of this study was to compare insulin glargine with isophane insulin (NPH insulin) for basal insulin supply in patients with type 1 diabetes. METHODS: A total of 48 type 1 diabetics on long term conventional intensive insulin therapy (IT) were randomized to three different regimens of basal insulin substitution: 1. continuation of NPH insulin once daily at bedtime with more intensive selfmonitoring (n = 15); 2. NPH insulin twice daily (n = 15); 3. insulin glargine once daily (n = 18). Meal time insulin aspart was continued in all groups. RESULTS: Fasting blood glucose (FBG) was lower in the glargine group (7.30+/-0.98 mmol/1) than in the twice daily NPH group (7.47+/-1.06 mmol/1), but without significant difference. FBG was significantly higher in the once daily NPH group (8.44+/-0.85 mmol/l; p < 0.05). HbAlc after 3 months did not change in the once daily NPH group, but decreased in the glargine group (from 7.72+/-0.86% to 6.87+/-0.50%), as well as in the twice daily NPH group (from 7.80+/-0.83% to 7.01+/-0.63%). Total daily insulin doses were similar in all groups but only in the glargine group there was an increase of basal and decrease of meal related insulin doses. The frequency of mild hypoglycemia was significantly lower in the glargine group (6.56+/-2.09) than in both NPH groups (9.0+/-1.65 in twice daily NPH group and 8.13+/-1.30 in other NPH group) (episodes/patients-month, p < 0.05). CONCLUSION: Basal insulin supplementation in type 1 diabetes mellitus with either twice daily NPH insulin or glargine can result in similar glycemic control when combined with meal time insulin aspart. However, with glargine regimen FBG, HbAlc and frequency of hypoglycemic event are lower. These facts contribute to better patients satisfaction with insulin glargine versus NPH insulin in IIT in type 1 diabetics.