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1.
Chemosphere ; 239: 124705, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31479913

RESUMO

Tamoxifen is a clinical drug for estrogen receptor (ER)-positive breast cancer. Recently, it has been detected in aquatic environment. The residual drugs will produce certain biological activity and create a risk to aquatic organism when they enter the water environment. Therefore, it has great significance to study the ecotoxicity of tamoxifen. In the study, we used zebrafish as a model of aquatic to investigate the ecotoxic mechanism of tamoxifen to aquatic. We found that tamoxifen induced liver lipid accumulation in zebrafish, which showed a significant hepatotoxicity with smaller liver area and bigger yolk area. Though biochemical and pathologic measurement, tamoxifen treated group showed higher transaminase and lipid content. The elevated liver lipid synthesis might due to the increase of lipid metabolism related gene Srebf1, Srebf2 and Fasn. Moreover, inflammatory cytokine Tnf-α, Il-1ß And Il-6 were increased. This result confirmed the toxicity of tamoxifen to aquatic, suggested liver injury was the main characteristic of its ecotoxicity. This study indicated it is important to avoid tamoxifen discharging into the aquatic ecology and provided a theoretical basis of prevention tamoxifen-induced ecotoxicity to aquatic.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/etiologia , Inflamação/induzido quimicamente , Metabolismo dos Lipídeos/efeitos dos fármacos , Tamoxifeno/efeitos adversos , Animais , Citocinas/metabolismo , Ecotoxicologia , Feminino , Humanos , Inflamação/complicações , Fígado/metabolismo , Fígado/patologia , Tamoxifeno/química , Poluentes Químicos da Água/efeitos adversos , Peixe-Zebra/metabolismo
2.
Cell Physiol Biochem ; 53(5): 805-819, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31670920

RESUMO

BACKGROUND/AIMS: Despite effective therapeutic strategies for treating hormone receptor-positive (HR+) breast cancer, resistance to endocrine therapy that is either de novo or acquired still occurs. We investigated epidermal growth factor receptor (EGFR) as a therapeutic target for overcoming endocrine resistance in HR+ breast cancer models. METHODS: Using clinical data from 2,166 patients who had HR+ breast tumors and received tamoxifen, we analyzed survival rates. Levels of mRNA and protein expression were analyzed by real-time PCR and western blotting, respectively. Cell viability was analyzed by MTT assays and anchorage-independent growth by soft agar colony-formation assays. Efficacy of tamoxifen and/or gefitinib was analyzed using orthotopic xenograft mouse models. RESULTS: EGFR expression was significantly associated with more advanced stage and higher grade. EGFR expression was different in luminal A-like (Lum A, 1.3%) versus luminal B-like (Lum B, 11.4%) subtypes. On multivariate analyses for survival Lum B subtype EGFR+ tumors showed a hazard ratio (HR) of 5.22 (95% CI, 1.29-21.15, P = 0.020) for overall survival (OS) and HR of 2.91 (95% CI, 1.35-6.28, P = 0.006) for disease-free survival (DFS). Levels of EGFR inversely correlated with ER-α expression. Basal ER-α level was completely blocked by TGFA or EGF treatment. With TGFA pretreatment, ER+ breast cancer cells were resistant to 4-hydroxytamoxifen (4-OHT). Conversely, downregulation of ER-α by TGFA was reversed by gefitinib with recovered sensitivity to 4-OHT. Tumorigenicity of EGFR and ER+ breast cancer cells were significantly decreased by combined tamoxifen and gefitinib. CONCLUSION: Aberrant EGFR expression was associated with poor prognosis in ER+ breast cancers, especially the Lum B subtype. Loss of ER by EGFR activation induced tamoxifen resistance. Therefore, EGFR could be a therapeutic target for overcoming recurrence of ER+ breast cancer with high EGFR expression.


Assuntos
Neoplasias da Mama/patologia , Receptor ErbB-2/metabolismo , Adulto , Idoso , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias da Mama/mortalidade , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Receptor ErbB-2/antagonistas & inibidores , Receptores Estrogênicos/metabolismo , Taxa de Sobrevida , Tamoxifeno/análogos & derivados , Tamoxifeno/química , Tamoxifeno/farmacologia
3.
Pharm Res ; 36(12): 170, 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31654151

RESUMO

PURPOSE: Many bioactive molecules show a type of solution phase behavior, termed promiscuous aggregation, whereby at micromolar concentrations, colloidal drug-rich aggregates are formed in aqueous solution. These aggregates are known to be a major cause of false positives and false negatives in select enzymatic high-throughput screening assays. The goal of this study was to investigate the impact of drug-rich aggregates on in vitro drug screening metabolism assays. METHODS: Cilnidipine was selected as an aggregate former and its impact on drug metabolism was evaluated against rCYP2D6, rCYP1A2, rCYP2C9 and human liver microsomes. RESULTS: The cilnidipine aggregates were shown to non-specifically inhibit multiple cytochrome P450 enzymes with an IC50 comparable with the IC50 of potent model inhibitors. CONCLUSIONS: This newly demonstrated mode of "promiscuous inhibition" is of great importance as it can lead to false positives during drug metabolism evaluations and thus it needs to be considered in the future to better predict in vivo drug-drug interactions.


Assuntos
Sistema Enzimático do Citocromo P-450/química , Di-Hidropiridinas/química , Microssomos Hepáticos/metabolismo , Proteínas Recombinantes/química , Carvedilol/química , Carvedilol/metabolismo , Coloides/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Diclofenaco/química , Diclofenaco/metabolismo , Di-Hidropiridinas/metabolismo , Interações de Medicamentos , Ensaios de Triagem em Larga Escala/métodos , Humanos , Concentração Inibidora 50 , Cinética , Taxa de Depuração Metabólica/efeitos dos fármacos , Fenacetina/química , Fenacetina/metabolismo , Proteínas Recombinantes/metabolismo , Solventes/química , Tamoxifeno/química , Tamoxifeno/metabolismo
4.
Planta Med ; 85(16): 1275-1286, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31627219

RESUMO

Breast cancer is one of the most common cancers diagnosed among women worldwide. Estrogen receptor alpha (ERα) is a transcriptional factor that plays an important role in the development and progression of breast cancer. Yuanhuatine, a natural daphnane-type diterpenoid extracted from Daphne genkwa, was reported to exhibit significant cytotoxicity against breast cancer cells. However, the underlying mechanism is still unclear. In this study, we evaluated the cytotoxicity of yuanhuatine on two breast cancer cell lines that are ERα-positive and -negative. The results show that yuanhuatine inhibits the growth of ERα-positive cells (MCF-7) with much stronger inhibitory activity (IC50 = 0.62 µM) compared with positive control tamoxifen (IC50 = 14.43 µM). However, no obvious cytotoxicity was observed in ERα-negative cells (MDA-MB-231). Subsequent experiment also indicated that yuanhuatine markedly induced mitochondrial dysfunction, leading to apoptosis in MCF-7 cells. Molecular docking studies suggest the potential interactions between yuanhuatine and ERα. Immunofluorescence staining and Western blot analysis indicated that yuanhuatine down-regulated the expression of ERα in MCF-7 cells. MPP, a specific ERα inhibitor, significantly enhanced yuanhuatine-induced mitochondrial dysfunction and apoptosis in MCF-7 cells. On the contrary, the treatment with yuanhuatine causes no apoptosis in MM231 cells. Altogether, in vitro and in silico results suggested that ERα down-regulation was involved in yuanhuatine-induced mitochondrial dysfunction and apoptosis in ERα-positive breast cancer cells. Thus, yuanhuatine could be a potential candidate for treating ERα-positive breast cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Daphne/química , Tamoxifeno/farmacologia , Antineoplásicos Fitogênicos/química , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Feminino , Humanos , Células MCF-7 , Mitocôndrias/metabolismo , Simulação de Acoplamento Molecular , Tamoxifeno/química
5.
PLoS One ; 14(7): e0219285, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31291309

RESUMO

Nanomedicine is an emerging area in the medical field, particularly in the treatment of cancers. Nanostructured lipid carrier (NLC) was shown to be a good nanoparticulated carrier for the delivery of tamoxifen (TAM). In this study, the tamoxifen-loaded erythropoietin-coated nanostructured lipid carriers (EPO-TAMNLC) were developed to enhance the anti-cancer properties and targetability of TAM, using EPO as the homing ligand for EPO receptors (EpoRs) on breast cancer tissue cells. Tamoxifen-loaded NLC (TAMNLC) was used for comparison. The LA7 cells and LA7 cell-induced rat mammary gland tumor were used as models in the study. Immunocytochemistry staining showed that LA7 cells express estrogen receptors (ERs) and EpoRs. EPO-TAMNLC and TAMNLC significantly (p<0.05) inhibited proliferation of LA7 in dose- and time-dependent manner. EPO-TAMNLC induced apoptosis and G0/G1 cell cycle arrest of LA7 cells. Both drug delivery systems showed anti-mammary gland tumor properties. At an intravenous dose of 5 mg kg-1 body weight, EPO-TAMNLC and TAMNLC were not toxic to rats, suggesting that both are safe therapeutic compounds. In conclusion, EPO-TAMNLC is not only a unique drug delivery system because of the dual drug-loading feature, but also potentially highly specific in the targeting of breast cancer tissues positive for ERs and EpoRs. The incorporation of TAM into NLC with and without EPO coat had significantly (p<0.05) improved specificity and safety of the drug carriers in the treatment of mammary gland tumors.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Receptores da Eritropoetina/química , Animais , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Humanos , Ligantes , Lipídeos/química , Lipídeos/farmacologia , Células MCF-7 , Glândulas Mamárias Animais/efeitos dos fármacos , Glândulas Mamárias Animais/patologia , Ratos , Receptores da Eritropoetina/genética , Tamoxifeno/química , Tamoxifeno/farmacologia
6.
Org Biomol Chem ; 17(19): 4892-4905, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-31041982

RESUMO

A series of 2,3,4-triaryl-substituted 1,2,4-oxadiazole-5-ones have been prepared as fixed-ring analogues of tamoxifen (TAM), a drug inhibitor of Estradiol Receptor (ER) used in breast cancer therapy, by an efficient synthetic protocol based on a 1,3-dipolar cycloaddition of nitrones to isocyanates. Some of the newly synthesized compounds (14d-f, 14h and 14k) show a significant cytotoxic effect in a human breast cancer cell line (MCF-7) possessing IC50 values between 15.63 and 31.82 µM. In addition, compounds 14d-f, 14h and 14k are able to increase the p53 expression levels, activating also the apoptotic pathway. Molecular modeling studies of novel compounds performed on the crystal structure of ER reveal the presence of strong hydrophobic interactions with the aromatic rings of the ligands similar to TAM. These data suggest that 1,2,4-oxadiazole-5-ones can be considered analogues of TAM, and that their anticancer activity might be partially due to ER inhibition.


Assuntos
Antineoplásicos Hormonais/síntese química , Antineoplásicos Hormonais/farmacologia , Oxidiazóis/síntese química , Oxidiazóis/farmacologia , Tamoxifeno/análogos & derivados , Antineoplásicos Hormonais/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Interações Hidrofóbicas e Hidrofílicas , Células MCF-7 , Estrutura Molecular , Oxidiazóis/química , Teoria Quântica , Relação Estrutura-Atividade , Tamoxifeno/química , Células Tumorais Cultivadas
7.
Biol Pharm Bull ; 42(3): 401-410, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30828072

RESUMO

Ridaifen (RID)-B is an analog derived from tamoxifen (TAM). TAM has an antitumor effect by acting as an antagonist to estrogen receptor (ER). However, TAM is known to also induces apoptosis in cancer cells that do not have ER. We clarified that RID-B induces cell death at a lower concentration than TAM, and causes ER-independent apoptosis and autophagy. Based on the results of previous studies, we assumed that RID-B had a unique target different from ER and examined structural activity correlation to determine what kinds of structural features are related to RID-B activity. As a result, we found there was activity even without one of phenyl groups (Ar3) in RID-B and revealed that two pyrrolidine side chains peculiar to RID-B are related to the action. Furthermore, analogs with shorter alkyl side chains induced autophagy, but analogs with certain length of alkyl side chains induced apoptosis. Also, although there is no doubt that RID-B induces apoptosis by causing mitochondrial injury, our results suggested that such injury induced mitochondria-selective autophagy. We revealed that RID-B induce mitophagy and that this mitophagy is a defense mechanism against RID-B. Our results suggest that autophagy was induced against apoptosis caused by mitochondrial dysfunction in RID-B, so the combination of autophagy inhibitor and anticancer-drug can be effective for cancer treatment.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Pirrolidinas/química , Pirrolidinas/farmacologia , Tamoxifeno/análogos & derivados , Actinas/genética , Actinas/metabolismo , Caspase 3/genética , Caspase 3/metabolismo , Linhagem Celular Tumoral , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Mitocôndrias/efeitos dos fármacos , Estrutura Molecular , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Tamoxifeno/química , Tamoxifeno/farmacologia
8.
Biomed Res Int ; 2019: 2161348, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30800663

RESUMO

We tested the solubility and dissolution of tamoxifen citrate to ascertain the optimal conditions for faster dissolution. Using the solvent evaporation method and hydrophilic carriers, we formulated tamoxifen citrate (TC) that contained solid dispersions (SDs). We increased the solubility and dissolution rate of TC with a solid dispersion system that consisted of polyethylene glycol (PEG-6000), beta-cyclodextrin (ß-CD), and a combination of carriers. Physicochemical characteristics of solubility (mg/ml) were found to be 0.987±0.04 (water), 1.324±0.05 (6.8pH PBS), and 1.156±0.03 (7.4 pH PBS) for F5 formulation, percentage yield was between 98.74 ± 1.11% and 99.06 ± 0.58%, drug content was between 98.06±0.58 and 99.06±1.10, and dissolution studies binary complex showed a faster release of TC as compared to a single polymer and pure drug. Furthermore, thermal properties, physicochemical drug and polymer interaction, crystal properties, and morphology were determined using differential scanning calorimetry (DSC), infrared spectroscopy (FT-IR), X-ray differential studies, and scanning electron microscopy. We used the same proportion of carrier concentrations of the formulations to calculate the solubility of TC. Our results demonstrated that increased concentrations of ß-C yielded an improved solubility of TC, which was two times higher than pure TC. The uniformity in drug content was 97.99 %. A quicker drug release occurred from the binary complex formulation as seen in the dissolution profile. FTIR demonstrated an absence in the physicochemical interaction between the drug and carriers. The drug was also found to be dispersed in the amorphous state as revealed by DSC and XRD. The drug concentration did not vary during various storage conditions. Our in vivo studies demonstrated that SD displayed significantly higher values of Cmax (p < 0.05) and AUC0-24 (p < 0.05) as compared to free TC. Furthermore, Tmax in SD was significantly lower (p < 0.05), as compared to free TC.


Assuntos
Solubilidade/efeitos dos fármacos , Tamoxifeno/química , Varredura Diferencial de Calorimetria/métodos , Química Farmacêutica/métodos , Portadores de Fármacos/química , Interações Hidrofóbicas e Hidrofílicas/efeitos dos fármacos , Microscopia Eletrônica de Varredura/métodos , Polietilenoglicóis/química , Polímeros/química , Solventes/química , Espectrofotometria Infravermelho/métodos , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Difração de Raios X/métodos , beta-Ciclodextrinas/química
9.
BMC Complement Altern Med ; 19(1): 23, 2019 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-30658716

RESUMO

BACKGROUND: Women diagnosed with breast cancer frequently seek complementary and alternative (CAM) treatment options that can help to cope with their disease and the side effects of conventional cancer therapy. Especially in Europe, breast cancer patients use herbal products containing mistletoe (Viscum album L.). The oldest and one of the most prescribed conventional drugs for the treatment of estrogen receptor positive breast cancer is tamoxifen. Aside from positive clinical experience with the combination of tamoxifen and mistletoe, little is known about possible herb-drug interactions (HDIs) between the two products. In the present in vitro study, we investigated the effect of standardized commercial mistletoe preparations on the activity of endoxifen, the major active metabolite of tamoxifen. METHODS: The estrogen receptor positive human breast carcinoma cell line MCF-7 was treated with (E/Z)-endoxifen hydrochloride in the presence and absence of a defined estradiol concentration. Each concentration of the drug was combined with fermented Viscum album L. extracts (VAE) at clinically relevant doses, and proliferation, apoptosis and cell cycle were analyzed. In parallel, possible inhibition of CYP3A4/5 and CYP2D6 was investigated using 50-donor mixed gender pooled human liver microsomes (HLMs). RESULTS: VAE did not inhibit endoxifen induced cytostasis and cytotoxicity. At higher concentrations, VAE showed an additive inhibitory effect. VAE preparations did not cause inhibition of CYP3A4/5 and CYP2D6 catalyzed tamoxifen metabolism. CONCLUSIONS: The in vitro results suggest that mistletoe preparations can be used in combination with tamoxifen without the risk of HDIs.


Assuntos
Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP3A/metabolismo , Extratos Vegetais/farmacologia , Tamoxifeno/análogos & derivados , Viscum album/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Interações Ervas-Drogas , Humanos , Células MCF-7 , Extratos Vegetais/química , Tamoxifeno/química , Tamoxifeno/farmacologia
11.
Biomed Chromatogr ; 33(4): e4451, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30536649

RESUMO

A highly sensitive, specific and rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) analytical method has been developed and validated for the determination of ospemifene in human plasma using ospemifene-d4 as an internal standard. Solid-phase extraction technique with Phenomenex Strata X-33 µm polymeric sorbent cartridges (30 mg/1 mL) was used to extract the analytes from the plasma. The chromatographic separation was achieved on Agilent Eclipse XDB-Phenyl, 4.6 × 75 mm, 3.5 µm column using the mobile phase composition of methanol and 20 mm ammonium formate buffer (90:10, v/v) at a flow rate of 0.9 mL/min. A detailed method validation was performed as per the US Food and Drug Administration guidelines and the calibration curve obtained was linear (r2  = 99) over the concentration range 5.02-3025 ng/mL. The API-4500 MS/MS was operated under multiple reaction monitoring mode during the analysis. The proposed method was successfully applied to a pharmacokinetic study in healthy human volunteers after oral administration of an ospemifene 60 mg tablet under fed conditions.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Tamoxifeno/análogos & derivados , Espectrometria de Massas em Tandem/métodos , Adulto , Estabilidade de Medicamentos , Feminino , Humanos , Limite de Detecção , Modelos Lineares , Masculino , Reprodutibilidade dos Testes , Tamoxifeno/sangue , Tamoxifeno/química , Tamoxifeno/farmacocinética , Adulto Jovem
12.
Biomed Chromatogr ; 33(4): e4462, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30536934

RESUMO

To date, several methods for the quantification of tamoxifen and its metabolites have been developed, most of which employ liquid chromatography tandem-mass spectrometry (LC-MS/MS). These methods are highly sensitive and reproducible, but are also time-consuming and require expensive equipment; one of their main disadvantages is matrix ionization effects. A more viable option, particularly in developing countries, is high-performance liquid chromatography coupled with UV or fluorescence detection. We developed and validated a method for simultaneous quantification of tamoxifen, endoxifen and 4-hydroxytamoxifen based on high-performance liquid chromatography with fluorescence detection in a reverse-phase column. The method is rapid (16 min plus 5 min of column re-equilibrium), accurate (80-100%) and precise (0.23-6.00%), and does not require any additional irradiation process. Sample pretreatment consists of protein precipitation with acetonitrile under alkaline conditions, employing only 200 µL plasma. The validated method's wide range allowed quantification of steady-state levels in patients under standard tamoxifen treatment (20 mg/day). This assay is ready for application in clinical studies and routine quantification of tamoxifen, endoxifen and 4-hydroxytamoxifen in healthcare institutions.


Assuntos
Antineoplásicos Hormonais/sangue , Neoplasias da Mama/tratamento farmacológico , Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Fluorescência/métodos , Tamoxifeno/sangue , Antineoplásicos Hormonais/química , Antineoplásicos Hormonais/uso terapêutico , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Limite de Detecção , Modelos Lineares , Reprodutibilidade dos Testes , Tamoxifeno/análogos & derivados , Tamoxifeno/química , Tamoxifeno/uso terapêutico
13.
Bioorg Med Chem Lett ; 29(3): 367-372, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30587451

RESUMO

Potent estrogen receptor ligands typically contain a phenolic hydrogen-bond donor. The indazole of the selective estrogen receptor degrader (SERD) ARN-810 is believed to mimic this. Disclosed herein is the discovery of ARN-810 analogs which lack this hydrogen-bond donor. These SERDs induced tumor regression in a tamoxifen-resistant breast cancer xenograft, demonstrating that the indazole NH is not necessary for robust ER-modulation and anti-tumor activity.


Assuntos
Antineoplásicos/farmacologia , Cinamatos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Indazóis/farmacologia , Receptores Estrogênicos/antagonistas & inibidores , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Tamoxifeno/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cinamatos/síntese química , Cinamatos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Indazóis/síntese química , Indazóis/química , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Estrutura Molecular , Receptores Estrogênicos/metabolismo , Moduladores Seletivos de Receptor Estrogênico/síntese química , Moduladores Seletivos de Receptor Estrogênico/química , Relação Estrutura-Atividade , Tamoxifeno/síntese química , Tamoxifeno/química
14.
Carbohydr Polym ; 206: 428-434, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30553342

RESUMO

Herein, multilayer polysaccharide films were proposed and characterized as biomaterials for the local and controlled release of an antitumoral drug. To that aim, multilayer films of alginate (Alg) and chitosan (Chi) were built up through spray assisted layer-by-layer (LbL) technique employing an automatic equipment. A specific drug against breast cancer, tamoxifen (TMX), was incorporated in different intermediate positions of the multilayer Alg/Chi films. Our findings highlight that Alg/Chi multilayer films can be employed for sustained and local TMX delivery and their therapeutic effect can be modulated and optimized by the number of bilayers deposited over the loaded tamoxifen, the quantity of tamoxifen loaded in several intermediate positions and the total area of the film.


Assuntos
Alginatos/química , Antineoplásicos/farmacologia , Quitosana/química , Preparações de Ação Retardada/química , Tamoxifeno/farmacologia , Alginatos/toxicidade , Antineoplásicos/química , Linhagem Celular Tumoral , Quitosana/toxicidade , Preparações de Ação Retardada/toxicidade , Difusão , Liberação Controlada de Fármacos , Humanos , Tamoxifeno/química , Molhabilidade
15.
J Mol Model ; 24(12): 336, 2018 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-30413890

RESUMO

Here, we report theoretical research into the interaction of the drug tamoxifen drug with tripeptides found in the tumor environment-specifically, asparagine-glycine-arginine (NGR) and arginine-glycine-aspartic acid (RGD). Reactivity parameters of these tripeptides were calculated and their intrinsic reactivities and cross-reactivities were analyzed. The interactions of the tripeptides with the nanodiamond-tamoxifen (ND-TAM) complex where the nanodiamond acts as a nanocarrier were also examined theoretically. In addition, their intestinal absorption was predicted based on the polar surface area. The results showed that tamoxifen interacts with RGD, and this interaction remained after the addition of the nanodiamond. An analysis of the chemical hardnesses of the tripeptides was carried out to explore their possible use as synthetic vectors when joined to the nanodiamond. Results indicated that NGR is the most stable of the tripeptides and could be used for active targeting. All calculations were implemented using the conceptual framework of density functional theory.


Assuntos
Teoria da Densidade Funcional , Oligopeptídeos/química , Tamoxifeno/química , Antineoplásicos Hormonais/química , Antineoplásicos Hormonais/metabolismo , Antineoplásicos Hormonais/farmacocinética , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos/efeitos dos fármacos , Humanos , Modelos Moleculares , Nanodiamantes/administração & dosagem , Nanodiamantes/química , Neoplasias/química , Neoplasias/metabolismo , Neoplasias/patologia , Oligopeptídeos/metabolismo , Oligopeptídeos/farmacocinética , Ligação Proteica/efeitos dos fármacos , Tamoxifeno/metabolismo , Tamoxifeno/farmacocinética , Termodinâmica , Microambiente Tumoral/efeitos dos fármacos
16.
Small ; 14(49): e1803262, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30307701

RESUMO

Despite the promises of applying nano-photosensitizers (nano-PSs) for photodynamic therapy (PDT) against cancer, severe tumor hypoxia and limited tumor penetration of nano-PSs would lead to nonoptimized therapeutic outcomes of PDT. Therefore, herein a biocompatible nano-PS is prepared by using tamoxifen (TAM), an anti-estrogen compound, to induce self-assembly of chlorin e6 (Ce6) modified human serum albumin (HSA). The formed HSA-Ce6/TAM nanocomplexes, which are stable under neutral pH with a diameter of ≈130 nm, would be dissociated into individual HSA-Ce6 and TAM molecules under the acidic tumor microenvironment, owing to the pH responsive transition of TAM from hydrophobic to hydrophilic. Upon systemic administration, such HSA-Ce6/TAM nanoparticles exhibit prolonged blood circulation and high accumulation in the tumor, where it would undergo rapid pH responsive dissociation to enable obviously enhanced intratumoral penetration of HSA-Ce6. Furthermore, utilizing the ability of TAM in reducing the oxygen consumption of cancer cells, it is found that HSA-Ce6/TAM after systemic administration could efficiently attenuate the tumor hypoxia status. Those effects acting together lead to remarkably enhanced PDT treatment. This work presents a rather simple approach to fabricate smart nano-PSs with multiple functions integrated into a single system via self-assembly of all-biocompatible components, promising for the next generation cancer PDT.


Assuntos
Albuminas/química , Fotoquimioterapia/métodos , Tamoxifeno/química , Linhagem Celular Tumoral , Humanos , Concentração de Íons de Hidrogênio , Hipóxia , Microambiente Tumoral/fisiologia
17.
Int J Biol Macromol ; 120(Pt B): 1525-1532, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30227209

RESUMO

A lentinan (LEN) functionalized multi-walled carbon nanotubes (MWCNTs) drug delivery system, using tamoxifen (TAM) as a model anticancer agent, was developed by a simple non-covalent approach. This developed system (MWCNTs-TAM-LEN) possessed good stability, water dispersibility and extraordinary photothermal properties. It was demonstrated by the in vitro experiments that MWCNTs-TAM-LEN had enhanced cellular uptake, antitumor activity and cell apoptosis on Mcf-7 cells in comparison with TAM and MWCNTs-TAM. The cell inhibition rate and apoptosis rate of Mcf-7 cells treated by MWCNTs-TAM-LEN with near-infrared (NIR) were 67.1% and 66.5% higher than that of equivalent concentration of TAM with NIR irradiation treatment, respectively. The enhanced antitumor efficacy of MWCNTs-TAM-LEN was realized via the synergistic function of chemotherapy and photothermal ablation under NIR laser irradiation.


Assuntos
Técnicas de Ablação , Portadores de Fármacos/química , Lentinano/química , Nanotubos de Carbono/química , Tamoxifeno/química , Tamoxifeno/farmacologia , Transporte Biológico , Terapia Combinada , Humanos , Células MCF-7 , Modelos Moleculares , Conformação Molecular , Tamoxifeno/metabolismo , Tamoxifeno/uso terapêutico
18.
AAPS PharmSciTech ; 19(7): 3287-3297, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30218267

RESUMO

Primary standard therapy for ER-positive breast cancer being tamoxifen, newer delivery approach for enhancement of dissolution and therapeutic efficiency of tamoxifen through oral route could be a possible solution. In the present study, we investigated combination of tamoxifen (TAM) with resveratrol (RES) and observed that the combination is effective on MCF-7 breast cancer cells. To ensure co-delivery of the drugs, we explored the hot melt extrusion technique for simultaneously extruding two drugs together in order to enhance their bioavailability. As both are class II drugs with dissolution limited bioavailability, detailed formulation and process parameter analyses were carried out. Detailed characterization using microscopy, Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and X-ray powder diffraction (XRD) confirmed that both the drugs were molecularly dispersed in the matrix of Soluplus, CremophorRH40, and Poloxamer188, and no interactions between the ingredients were there during hot melt extrusion (HME) process. Dissolution studies confirmed that HME extrudates were able to release drug more rapidly than simple suspension formulation. Further, pharmacokinetic studies in rats were carried out for tamoxifen. Results demonstrated that extrusion significantly increased the tamoxifen oral bioavailability (p < 0.05) (Tmax = 2.00 ± 0.56 h, Cmax = 3.66 ± 1.49 µg/mL, AUC = 39.80 ± 16.24 µg h/mL, MRT = 20.49 ± 5.71) compared to the conventional suspension of tamoxifen (Tmax = 2.00 ± 0.71 h, Cmax = 2.41 ± 0.84 µg/mL, AUC = 12.82 ± 3.99 µg h/mL, MRT = 18.24 ± 5.95 h). In vitro cytotoxicity studies of TAM, RES, and their combination (TAM-RES) were evaluated with MCF7 cells. The combination showed significantly lower IC50 compared to TAM with increasing ratio of RES which is a result of apoptosis. HME-based simultaneous extrusion of TAM and RES formulation provides a suitable formulation strategy for breast cancer treatment and establishes proof of concept for extruding multiple drugs simultaneously for other applications in future.


Assuntos
Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Neoplasias da Mama , Desenvolvimento de Medicamentos/métodos , Resveratrol/administração & dosagem , Tamoxifeno/administração & dosagem , Administração Oral , Animais , Antineoplásicos Hormonais/química , Antineoplásicos Hormonais/metabolismo , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/química , Protocolos de Quimioterapia Combinada Antineoplásica/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Varredura Diferencial de Calorimetria/métodos , Química Farmacêutica/métodos , Sinergismo Farmacológico , Temperatura Alta , Humanos , Células MCF-7 , Ratos , Ratos Sprague-Dawley , Resveratrol/química , Resveratrol/metabolismo , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Tamoxifeno/química , Tamoxifeno/metabolismo , Difração de Raios X/métodos
19.
Biomed Chromatogr ; 32(12): e4366, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30120785

RESUMO

Coadministration of tamoxifen citrate (TMC) and medroxyprogesterone acetate (MPA) is preferred to increase the response rate and the percentage recovery in patients with endometrial carcinoma. Administration of TMC and MPA and their combination affects estrogen and progestin receptor concentrations in advanced endometrium carcinoma by affecting 17ß-hydroxyl steroid dehydrogenase activity and serum hormone concentrations. A sensitive, accurate and robust thin-layer chromatography method has been established for simultaneous analysis of TMC and MPA. Method development was carried out on silica gel F254 using butanol-acetic acid-water (6:0.5:0.5, v/v/v) as mobile phase. Densitometric scanning was carried out at 241 nm for simultaneous detection of TMC and MPA. Retardation factor (Rf ) values for TMC and MPA were 0.21 and 0.85, respectively. The method was validated according to ICH guidelines. Regression plots revealed linear relationships in the concentration range of 50-500 and 25-250 ng/band for TMC and MPA, successively. Accuracy was ≥99.60 and 98.72% for TMC and MPA, respectively. Forced degradation studies using UV photodegradation was applied on MPA after exposure to UV light for different times and applying a kinetic study for calculating the degradation rate constant (k) and half-life time (t1/2 ).


Assuntos
Cromatografia em Camada Delgada/métodos , Densitometria/métodos , Acetato de Medroxiprogesterona/sangue , Tamoxifeno/sangue , Animais , Estabilidade de Medicamentos , Feminino , Cinética , Limite de Detecção , Modelos Lineares , Acetato de Medroxiprogesterona/química , Coelhos , Reprodutibilidade dos Testes , Tamoxifeno/química , Raios Ultravioleta
20.
Bioorg Med Chem ; 26(15): 4428-4440, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-30078609

RESUMO

Hybrid antiestrogen/histone deacetylase (HDAC) inhibitors were designed by appending zinc binding groups to the 4-hydroxystilbene core of 4-hydroxytamoxifen. The resulting hybrids were fully bifunctional, and displayed high nanomolar to low micromolar IC50 values against both the estrogen receptor α (ERα) and HDACs in vitro and in cell-based assays. The hybrids were antiproliferative against ER+ MCF-7 breast cancer cells, with hybrid 28b possessing an improved activity profile compared to either 4-hydroxytamoxifen or SAHA. Hybrid 28b displayed gene expression patterns that reflected both ERα and HDAC inhibition.


Assuntos
Desenho de Drogas , Antagonistas de Estrogênios/química , Inibidores de Histona Desacetilases/química , Histona Desacetilases/metabolismo , Tamoxifeno/química , Sítios de Ligação , Proliferação de Células/efeitos dos fármacos , Receptor alfa de Estrogênio/antagonistas & inibidores , Receptor alfa de Estrogênio/metabolismo , Histona Desacetilases/química , Humanos , Concentração Inibidora 50 , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Células MCF-7 , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Tamoxifeno/síntese química , Tamoxifeno/farmacologia , Zinco/química
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