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1.
Medicine (Baltimore) ; 99(2): e18550, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31914031

RESUMO

BACKGROUND: Adjuvant endocrine therapy is a vital portion of postoperative comprehensive treatment for breast cancer patients. In recent years, studies have shown that endocrine therapy has a certain impact on the serum lipids of breast cancer patients, and the changes of lipid profiles may bring a series of problems. However, very few studies focus on this issue to date. The results of these studies are inconsistent, and the influence of different adjuvant endocrine modalities on lipid profiles still remains controversial. In order to better explore this issue, we conduct this network meta-analysis. METHOD: The protocol followed preferred reporting items for systematic reviews and meta-analyses protocols. Three main databases (PubMed, Embase, and the Cochrane Library) will be searched systematically for eligible randomized controlled trials without language restriction. In addition, a manual search of the references of relevant published studies will also be considered. Two reviewers will conduct studies selection, data extraction, and risk of bias assessment independently. The primary outcome is the variation of biochemical parameters - the serum lipid profiles (cholesterol, triglyceride, high-density lipoprotein, low low-density lipoprotein). RESULTS: The results will provide useful information about the side effects of different adjuvant endocrine drugs on lipid profiles in postoperative breast cancer patients (estrogen receptor-positive and/or progesterone receptor-positive). CONCLUSION: The findings of this study will be published in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42019129850.


Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Lipídeos/sangue , Anastrozol/farmacologia , Anastrozol/uso terapêutico , Androstadienos/farmacologia , Androstadienos/uso terapêutico , Inibidores da Aromatase/farmacologia , Inibidores da Aromatase/uso terapêutico , Quimioterapia Adjuvante , Humanos , Letrozol/farmacologia , Letrozol/uso terapêutico , Meta-Análise em Rede , Projetos de Pesquisa , Tamoxifeno/farmacologia , Tamoxifeno/uso terapêutico , Toremifeno/farmacologia , Toremifeno/uso terapêutico
2.
Cancer Sci ; 111(1): 47-58, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31710162

RESUMO

Breast cancer is the most prevalent malignancy among women. Although endocrine therapy is effective, the development of endocrine resistance is a major clinical challenge. The tumor microenvironment (TME) promotes tumor malignancy, and tumor-associated macrophages (TAM) within the TME play a crucial role in endocrine resistance. Herein, we aimed to elucidate the relationship between TAM and the endocrine-resistant phenotype of breast cancer. Macrophages were cultured with conditioned medium (CM) from tamoxifen-sensitive (MCF7-S) or -resistant (MCF7-R) MCF7 breast cancer cells. M2 polarization was detected by CD163 immunofluorescence. To determine the effect on endocrine resistance, MCF7 cells were cultured in the supernatant of different TAM, and then treated with tamoxifen. CC-chemokine ligand 2 (CCL2) immunohistochemistry was carried out on pathological sections from 100 patients with invasive estrogen receptor-positive breast cancer. We found that macrophages cultured in the CM of MCF7-S and MCF7-R cells were induced into TAM, with a more obvious M2 polarization in the latter. Tamoxifen resistance was increased by culture in TAM medium. TAM secreted CCL2, which increased endocrine resistance in breast cancer cells through activation of the PI3K/Akt/mTOR signaling pathway. High expression of CCL2 was correlated with infiltration of CD163+macrophages (r = 0.548, P < .001), and patients with high CCL2 expression presented shorter progression-free survival than those with low CCL2 expression (P < .05). We conclude that CCL2 secreted by TAM activates PI3K/Akt/mTOR signaling and promotes an endocrine resistance feedback loop in the TME, suggesting that CCL2 and TAM may be novel therapeutic targets for patients with endocrine-resistant breast cancer.


Assuntos
Neoplasias da Mama/genética , Quimiocina CCL2/genética , Resistencia a Medicamentos Antineoplásicos/genética , Macrófagos/metabolismo , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Antígenos CD/genética , Antígenos de Diferenciação Mielomonocítica/genética , Antineoplásicos Hormonais/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Células MCF-7 , Intervalo Livre de Progressão , Receptores de Superfície Celular/genética , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/genética , Tamoxifeno/farmacologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética
3.
Int J Cancer ; 146(6): 1674-1685, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31340060

RESUMO

G protein-coupled estrogen receptor-1 (GPER), a member of the G protein-coupled receptor (GPCR) superfamily, mediates estrogen-induced proliferation of normal and malignant breast epithelial cells. However, its role in breast cancer stem cells (BCSCs) remains unclear. Here we showed greater expression of GPER in BCSCs than non-BCSCs of three patient-derived xenografts of ER- /PR+ breast cancers. GPER silencing reduced stemness features of BCSCs as reflected by reduced mammosphere forming capacity in vitro, and tumor growth in vivo with decreased BCSC populations. Comparative phosphoproteomics revealed greater GPER-mediated PKA/BAD signaling in BCSCs. Activation of GPER by its ligands, including tamoxifen (TMX), induced phosphorylation of PKA and BAD-Ser118 to sustain BCSC characteristics. Transfection with a dominant-negative mutant BAD (Ser118Ala) led to reduced cell survival. Taken together, GPER and its downstream signaling play a key role in maintaining the stemness of BCSCs, suggesting that GPER is a potential therapeutic target for eradicating BCSCs.


Assuntos
Neoplasias da Mama/patologia , Células-Tronco Neoplásicas/patologia , Receptores Estrogênicos/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Animais , Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Feminino , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Fosforilação/efeitos dos fármacos , Receptores Estrogênicos/genética , Receptores Acoplados a Proteínas-G/agonistas , Receptores Acoplados a Proteínas-G/genética , Receptores de Progesterona/metabolismo , Transdução de Sinais/efeitos dos fármacos , Esferoides Celulares , Tamoxifeno/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína de Morte Celular Associada a bcl/metabolismo
4.
Nat Commun ; 10(1): 5678, 2019 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-31831729

RESUMO

As a protective mechanism, the cornea is sensitive to noxious stimuli. Here, we show that in mice, a high proportion of corneal TRPM8+ cold-sensing fibers express the heat-sensitive TRPV1 channel. Despite its insensitivity to cold, TRPV1 enhances membrane potential changes and electrical firing of TRPM8+ neurons in response to cold stimulation. This elevated neuronal excitability leads to augmented ocular cold nociception in mice. In a model of dry eye disease, the expression of TRPV1 in TRPM8+ cold-sensing fibers is increased, and results in severe cold allodynia. Overexpression of TRPV1 in TRPM8+ sensory neurons leads to cold allodynia in both corneal and non-corneal tissues without affecting their thermal sensitivity. TRPV1-dependent neuronal sensitization facilitates the release of the neuropeptide substance P from TRPM8+ cold-sensing neurons to signal nociception in response to cold. Our study identifies a mechanism underlying corneal cold nociception and suggests a potential target for the treatment of ocular pain.


Assuntos
Córnea/metabolismo , Nociceptividade/fisiologia , Células Receptoras Sensoriais/metabolismo , Substância P/metabolismo , Canais de Cátion TRPV/metabolismo , Sensação Térmica/fisiologia , Animais , Temperatura Baixa , Síndromes do Olho Seco , Regulação da Expressão Gênica , Hiperalgesia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Receptoras Sensoriais/efeitos dos fármacos , Canais de Cátion TRPV/genética , Tamoxifeno/farmacologia
5.
Pharm Res ; 37(1): 7, 2019 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-31845095

RESUMO

PURPOSE: Antidepressants like the serotonin reuptake inhibitors (SRIs) are often used concomitantly with tamoxifen (e.g. for treatment of depression). This may lead to an additional prolongation of the QTc-interval, with an increased risk of cardiac side effects. Therefore we investigated whether there is a drug-drug interaction between tamoxifen and SRIs resulting in a prolonged QTc-interval. METHODS: Electrocardiograms (ECGs) of 100 patients were collected at steady state tamoxifen treatment, with or without concomitant SRI co-medication. QTc-interval was manually measured and calculated using the Fridericia formula. Primary outcome was difference in QTc-interval between tamoxifen monotherapy and tamoxifen concomitantly with an SRI. RESULTS: The mean QTc-interval was 12.4 ms longer when tamoxifen was given concomitantly with an SRI (95% CI:1.8-23.1 ms; P = 0.023). Prolongation of the QTc-interval was particularly pronounced for paroxetine (17.2 ms; 95%CI:1.4-33.0 ms; P = 0.04), escitalopram (12.5 ms; 95%CI:4.4-20.6 ms; P < 0.01) and citalopram (20.7 ms; 95%CI:0.7-40.7 ms; P = 0.047), where other agents like venlafaxine did not seem to prolong the QTc-interval. None of the patients had a QTc-interval of >500 ms. CONCLUSIONS: Concomitant use of tamoxifen and SRIs resulted in a significantly higher mean QTc-interval, which was especially the case for paroxetine, escitalopram and citalopram. When concomitant administration with an SRI is warranted venlafaxine is preferred.


Assuntos
Antidepressivos de Segunda Geração/farmacologia , Antineoplásicos Hormonais/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/fisiopatologia , Inibidores de Captação de Serotonina/efeitos adversos , Tamoxifeno/efeitos adversos , Idoso , Antidepressivos de Segunda Geração/efeitos adversos , Antineoplásicos Hormonais/farmacologia , Neoplasias da Mama/complicações , Citalopram/farmacologia , Feminino , Humanos , Síndrome do QT Longo/induzido quimicamente , Pessoa de Meia-Idade , Inibidores de Captação de Serotonina/farmacologia , Tamoxifeno/farmacologia
6.
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
7.
Bratisl Lek Listy ; 120(10): 752-756, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31663350

RESUMO

AIM: Tamoxifen engages mitochondrial estrogen receptor beta as an antagonist, increases mitochondrial cytotoxicity and induces tumor cell death. Tamoxifen also engages plasma membrane estrogen receptor alpha as an agonist, while it is suggested that in some users its activation is put into action by mechanism of resistance to tamoxifen. Apoptotic inducers have been shown to promote tamoxifen-induced cell death, which might be of great importance in overcoming tamoxifen resistance. Considering the pleiotropic effects of statins, in the present study, we investigated the effects of atorvastatin on tamoxifen-induced intrinsic apoptotic pathway activity in melanoma cells. METHODS: Melanoma B16F10 cells were treated for 24 and 48 h with various concentrations of tamoxifen, atorvastatin and combination of tamoxifen + atorvastatin. Cells with no treatment were considered a control group, and the study was then followed by quantitative RT- PCR assay. Bax and cytochrome c gene expressions were calculated by ΔΔct method. RESULTS: Co-treatment of atorvastatin + tamoxifen could strongly enhance the expression of pro/apoptotic factors of Bax and cytochrome c in melanoma cells compared to the tamoxifen and atorvastatin groups. CONCLUSION: In general, we conclude that the atorvastatin-induced increase in Bax and cytochrome c gene expression might be a permissive response to tamoxifen-induced cell death (Fig. 2, Ref. 37).


Assuntos
Apoptose/efeitos dos fármacos , Atorvastatina/farmacologia , Melanoma Experimental , Tamoxifeno/farmacologia , Animais , Linhagem Celular Tumoral , Citocromos c/metabolismo , Sinergismo Farmacológico , Camundongos , Proteína X Associada a bcl-2/metabolismo
8.
Exp Eye Res ; 189: 107826, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31586450

RESUMO

PURPOSE: To investigate the potential protective effect of novel G protein coupled estrogen receptor (GPER1) against the neurotoxicity induced by NMDA in the mouse retina. METHODS: We induce retinal ganglion cells (RGCs) toxic injury through intravitreal injection of NMDA or acute ocular hypertension (AOH) induced by anterior chamber infusion with saline. Endogenous ligand 17-ß-estradiol (E2), GPER1 agonist (G-1), and E2 with GPER1 antagonist (G-15) or classic estrogen receptor α and ß (ERα and ERß) antagonist tamoxifen (TAM) were subcutaneous administered before NMDA to identify the possible involved receptors. Immunofluorescence staining was performed to explore the survival of RGCs and Müller cell gliosis. TUNEL staining was used to evaluate the RGC apoptosis. The involved molecular pathway was detected via antibody array expression profiling. RESULTS: Activation of estrogen receptor by E2 or G-1 could significantly rescue the RGCs injury in NMDA administration. The protective effect was carried exclusively by GPER1 activation. E2 application can still mimicked the protective function when estrogen receptor α and ß (ERα and ERß) blocked by tamoxifen (TAM), while the effects was blocked by GPER1 antagonist G-15. Moreover, the TUNEL positive RGCs and GFAP expression level were both attenuated in G-1 application and the effects could be reversed by G-15. In addition, application of the PI3K/Akt antagonist LY294002 counteracted the effect of G-1. And a number of apoptosis regulatory factors decreased dramatically in the G-1 group, including Bad, Caspase 3, Caspase 7, Smad2, P-53 and TAK1. Also, similar protective effect of G-1 was spotted in acute ocular hypertension (AOH) model. CONCLUSION: Estrogen played a protective role via a novel estrogen receptor, GPER1, instead of classical receptors ERα or ERß. Activation of GPER1 attenuated RGCs apoptosis and Müller cells gliosis, indicating GPER1 as a potential treatment target in RGCs degeneration diseases.


Assuntos
Regulação da Expressão Gênica , RNA/genética , Receptores Estrogênicos/genética , Receptores Acoplados a Proteínas-G/genética , Degeneração Retiniana/genética , Células Ganglionares da Retina/metabolismo , Tamoxifeno/farmacologia , Animais , Apoptose , Western Blotting , Modelos Animais de Doenças , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , N-Metilaspartato/toxicidade , RNA/metabolismo , Receptores Estrogênicos/biossíntese , Receptores Estrogênicos/efeitos dos fármacos , Receptores Acoplados a Proteínas-G/biossíntese , Receptores Acoplados a Proteínas-G/efeitos dos fármacos , Degeneração Retiniana/tratamento farmacológico , Degeneração Retiniana/metabolismo , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/patologia , Moduladores Seletivos de Receptor Estrogênico/farmacologia
9.
Med Sci Monit ; 25: 7872-7881, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31631887

RESUMO

BACKGROUND Heterotopic ossification (HO) is a kind of abnormal mineralized bone which usually occurs in muscle, tendon, or ligament. There are currently no effective drugs for the treatment and prevention of HO. Developing effective drugs that can inhibit HO is of profound significance and would provide new strategies for clinical treatment of this disease. The present investigation evaluated the inhibitory effect of tamoxifen against HO. MATERIAL AND METHODS Using an Achilles tendon trauma-induced HO female mice model, we screened different doses of tamoxifen (1, 3, and 9 mg/kg) in mice to determine the optimal dosage on the inhibition of the HO formation. The curative effect of tamoxifen was also illustrated at different HO progression stages including inflammation, chondrogenesis, osteogenesis, and HO maturation. RESULTS Heterotopic bone was formed with typical endochondral ossification in Achilles tendons 6 weeks after surgery and continued to enlarge up to 12 weeks. The formation of HO was significantly inhibited with the treatment of tamoxifen at the dosage of 9 mg/kg, whereas 1 mg/kg and 3 mg/kg did not reduce HO bone volume remarkably. The progression of HO was both attenuated by tamoxifen from Day 1 and Week 4 post-surgery, whereas no inhibitory effect was shown at the osteogenesis and maturation stages treated with tamoxifen. CONCLUSIONS Tamoxifen exerts an inhibitory effect on the heterotopic bone progression at inflammation and chondrogenesis stages, with the TGF-ß signaling pathway suppressed following the increase in estrogen receptor alpha activity.


Assuntos
Tendão do Calcâneo/efeitos dos fármacos , Ossificação Heterotópica/tratamento farmacológico , Tamoxifeno/farmacologia , Animais , Osso e Ossos/metabolismo , China , Condrogênese/efeitos dos fármacos , Modelos Animais de Doenças , Progressão da Doença , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Músculos/metabolismo , Ossificação Heterotópica/metabolismo , Osteogênese/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Tamoxifeno/metabolismo , Traumatismos dos Tendões/tratamento farmacológico
10.
J Exp Clin Cancer Res ; 38(1): 414, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31601253

RESUMO

BACKGROUND: Tamoxifen resistance presents a huge clinical challenge for breast cancer patients. An understanding of the mechanisms of tamoxifen resistance can guide development of efficient therapies to prevent drug resistance. METHODS: We first tested whether peptidylarginine deiminase 2 (PAD2) may be involved in tamoxifen-resistance in breast cancer cells. The effect of depleting or inhibiting PAD2 in tamoxifen-resistant MCF-7 (MCF7/TamR) cells was evaluated both in vitro and in vivo. We then investigated the potential of Cl-amidine, a PAD inhibitor, to be used in combination with tamoxifen or docetaxel, and further explored the mechanism of the synergistic and effective drug regimen of PADs inhibitor and docetaxel on tamoxifen-resistant breast cancer cells. RESULTS: We report that PAD2 is dramatically upregulated in tamoxifen-resistant breast cancer. Depletion of PAD2 in MCF7/TamR cells facilitated the sensitivity of MCF7/TamR cells to tamoxifen. Moreover, miRNA-125b-5p negatively regulated PAD2 expression in MCF7/TamR cells, therefore overexpression of miR-125b-5p also increased the cell sensitivity to tamoxifen. Furthermore, inhibiting PAD2 with Cl-amidine not only partially restored the sensitivity of MCF7/TamR cells to tamoxifen, but also more efficiently enhanced the efficacy of docetaxel on MCF7/TamR cells with lower doses of Cl-amidine and docetaxel both in vivo and in vivo. We then showed that combination treatment with Cl-amidine and docetaxel enhanced p53 nuclear accumulation, which synergistically induced cell cycle arrest and apoptosis. Meanwhile, p53 activation in the combination treatment also accelerated autophagy processes by synergistically decreasing the activation of Akt/mTOR signaling, thus enhancing the inhibition of proliferation. CONCLUSION: Our results suggest that PAD2 functions as an important new biomarker for tamoxifen-resistant breast cancers and that inhibiting PAD2 combined with docetaxel may offer a new approach to treatment of tamoxifen-resistant breast cancers.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/tratamento farmacológico , Docetaxel/farmacologia , Tamoxifeno/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose , Autofagia , Neoplasias da Mama/enzimologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células , Docetaxel/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Ornitina/análogos & derivados , Ornitina/farmacologia , Ornitina/uso terapêutico , /metabolismo , Tamoxifeno/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
11.
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
12.
BMC Complement Altern Med ; 19(1): 240, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31484532

RESUMO

BACKGROUND: Major depression is an important complication in patients with breast cancer, but is an underrecognized and undertreated condition in this population. The Baihe Zhimu Tang (BZ formula) is a traditional Chinese formula consisting of Lilium brownii var. viridulum Baker (L. brownii) and Anemarrhena asphodeloides (A. asphodeloides) Bunge that is used for the treatment of depression. However, the interaction between tamoxifen and BZ formula is frequently overlooked by traditional and alternative medical doctors. In the present study, the influence of BZ formula on the effectiveness of tamoxifen in breast cancer in mice and the effects of tamoxifen on the antidepressant effect of BZ formula and its major components mangiferin and timosaponin BII in mice were investigated. METHODS: Identification of the major components of BZ formula was performed using fast HPLC-tandem mass spectrometry (HPLC-MS/MS). The main flavonoids and saponins in A. asphodeloides were determined by HPLC-UV and HPLC-ELSD, separately. The antidepressant efficacy of BZ formula was evaluated using a mouse tail-suspension test. The effects of BZ formula on the antineoplastic activity of tamoxifen were performed in a mouse xenograft model of human breast cancer MCF-7 cells. P450 activity was determined using microsomal incubations by HPLC-MS/MS. Measurement of serum concentrations of tamoxifen and its metabolites was used by HPLC-MS/MS. RESULTS: BZ formula attenuated the effectiveness of tamoxifen treatment of breast cancer and reduced the concentrations of endoxifen and 4-OH-tamoxifen in tumor-bearing mice. Of two of the major components of BZ formula, the antidepressant effect of mangiferin, but not timosaponin BII, was significantly inhibited by tamoxifen in mice. BZ formula and its component mangiferin also significantly inhibited CYP450 enzyme activity in rat liver microsomes. CONCLUSION: BZ formula attenuated the effectiveness of tamoxifen in treatment of breast cancer in mice by influencing CYP450 enzymes. The present study laid a foundation for the treatment of patients with breast cancer and depression by BZ formula or other Chinese herbal formulas containing A. asphodeloides.


Assuntos
Antineoplásicos Hormonais/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Neoplasias Mamárias Experimentais/metabolismo , Tamoxifeno/farmacologia , Animais , Antineoplásicos Hormonais/farmacocinética , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Depressão/metabolismo , Interações de Medicamentos , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacocinética , Feminino , Humanos , Células MCF-7 , Masculino , Camundongos , Camundongos Endogâmicos ICR , Camundongos Nus , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Ratos , Tamoxifeno/farmacocinética
13.
Oncogene ; 38(43): 6913-6925, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31406251

RESUMO

Metastatic, antiestrogen resistant estrogen receptor α positive (ER+) breast cancer is the leading cause of breast cancer deaths in USA women. While studies have demonstrated the importance of the stromal tumor microenvironment in cancer progression and therapeutic responses, effects on the responses of ER+ cancers to estrogen and antiestrogens are poorly understood, particularly in the complex in vivo environment. In this study, we used an estrogen responsive syngeneic mouse model to interrogate how a COL1A1-enriched fibrotic ECM modulates integrated hormonal responses in cancer progression. We orthotopically transplanted the ER+ TC11 cell line into wild-type (WT) or collagen-dense (Col1a1tm1Jae/+, mCol1a1) syngeneic FVB/N female mice. Once tumors were established, recipients were supplemented with 17ß-estradiol (E2), tamoxifen, or left untreated. Although the dense/stiff environment in mCol1a1 recipients did not alter the rate of E2-induced proliferation of the primary tumor, it fostered the agonist activity of tamoxifen to increase proliferation and AP-1 activity. Manipulation of estrogen activity did not alter the incidence of lung lesions in either WT or mCol1a1 hosts. However, the mCol1a1 environment enabled tamoxifen-stimulated growth of pulmonary metastases and further fueled estrogen-driven growth. Moreover, E2 remodeled peritumoral ECM architecture in WT animals, modifying alignment of collagen fibers and altering synthesis of ECM components associated with increased alignment and stiffness, and increasing FN1 and POSTN expression in the pulmonary metastatic niche. These studies demonstrate dynamic interactions between ECM properties and estrogen activity in progression of ER+ breast cancer, and support the need for therapeutics that target both ER and the tumor microenvironment.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Receptor alfa de Estrogênio/metabolismo , Estrogênios/metabolismo , Matriz Extracelular/metabolismo , Animais , Neoplasias da Mama/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Progressão da Doença , Estradiol/metabolismo , Antagonistas de Estrogênios/farmacologia , Matriz Extracelular/efeitos dos fármacos , Feminino , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Camundongos , Tamoxifeno/farmacologia , Microambiente Tumoral/efeitos dos fármacos
14.
J Mol Model ; 25(9): 278, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31463793

RESUMO

Estrogen receptor (ER) is a nuclear hormone receptor and plays an important role in mediating the cellular effects of estrogen. ER can be classified into two receptors: estrogen receptor alpha (ERα) and beta (ERß), and the former is expressed in 50~80% of breast tumors and has been extensively investigated in breast cancer for decades. Excessive exposure to estrogen can obviously stimulate the growth of breast cancers primarily mediated by ERα, and thus anti-estrogen therapies by small molecules are of concern to clinicians and pharmaceutical industry in the treatment of ERα-positive breast cancers. Although a series of estrogen receptor modulators have been developed, these drugs can lead to resistance and side effects. Therefore, the development of small molecule inhibitors with high target specificity has been intensified. In this pursuit, an integrated computer-aided virtual screening technique, including molecular docking and pharmacophore model screening, was used to screen traditional Chinese medicine (TCM) databases. The compounds with high docking scores and fit values were subjected to ADME (adsorption, distribution, metabolism, excretion) and toxicity prediction, and ten hits were identified as potential inhibitors targeting ERα. Molecular docking was used to investigate the binding modes between ERα and three most potent hits, and molecular dynamic simulations were chosen to explore the stability of these complexes. The rank of the predicted binding free energies evaluated by MM/GBSA is consistent with the docking score. These novel scaffolds discovered in the present study can be used as critical starting point in the drug discovery process for treating ERα-positive breast cancer. Graphical abstract .


Assuntos
Antagonistas de Estrogênios/farmacologia , Receptor alfa de Estrogênio/antagonistas & inibidores , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Antineoplásicos Hormonais/farmacologia , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Avaliação Pré-Clínica de Medicamentos , Antagonistas de Estrogênios/uso terapêutico , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Ligantes , Medicina Tradicional Chinesa , Conformação Proteica , Tamoxifeno/farmacologia , Tamoxifeno/uso terapêutico
15.
Adv Exp Med Biol ; 1152: 229-241, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31456186

RESUMO

A large proportion of breast cancer patients are estrogen receptor positive. They generally benefit from tamoxifen, the drug that targets estrogen receptor signaling. However, de novo and acquired resistance against tamoxifen is well known. A number of signaling pathways and de-regulated factors have been evaluated to better understand the mechanism(s) of tamoxifen resistance. For past several years, non-coding RNAs have also gained attention as the putative regulators and determinants of tamoxifen resistance. A number of reports have documented evidence from in vitro and/or in vivo studies, as well as from evaluation of clinical samples, to showcase the power of non-coding RNAs as mediators of tamoxifen resistance and the predictors of disease relapse. This article puts into perspective the available information on microRNAs and the long non-coding RNAs regarding their ability to tweak resistance vs. sensitivity to tamoxifen.


Assuntos
Neoplasias da Mama/genética , Resistencia a Medicamentos Antineoplásicos/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Tamoxifeno/farmacologia , Antineoplásicos Hormonais/farmacologia , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos
16.
Molecules ; 24(13)2019 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-31284561

RESUMO

Melanoma is the leading cause of skin-cancer related deaths in North America. Metastatic melanoma is difficult to treat and chemotherapies have limited success. Furthermore, chemotherapies lead to toxic side effects due to nonselective targeting of normal cells. Curcumin is a natural product of Curcuma longa (turmeric) and has been shown to possess anti-cancer activity. However, due to its poor bioavailability and stability, natural curcumin is not an effective cancer treatment. We tested synthetic analogs of curcumin that are more stable. One of these derivatives, Compound A, has shown significant anti-cancer efficacy in colon, leukemia, and triple-negative inflammatory breast cancer cells. However, the effects of Compound A against melanoma cells have not been studied before. In this study, for the first time, we demonstrated the efficacy of Compound A for the selective induction of apoptosis in melanoma cells and its interaction with tamoxifen, taxol, and cisplatin. We found that Compound A induced apoptosis selectively in human melanoma cells by increasing oxidative stress. The anti-cancer activity of Compound A was enhanced when combined with tamoxifen and the combination treatment did not result in significant toxicity to noncancerous cells. Additionally, Compound A did not interact negatively with the anti-cancer activity of taxol and cisplatin. These results indicate that Compound A could be developed as a selective and effective melanoma treatment either alone or in combination with other non-toxic agents like tamoxifen.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Curcumina/farmacologia , Interações de Medicamentos , Antineoplásicos Fitogênicos/síntese química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/farmacologia , Curcumina/análogos & derivados , Curcumina/síntese química , Relação Dose-Resposta a Droga , Humanos , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Melanoma/patologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Estrutura Molecular , Estresse Oxidativo/efeitos dos fármacos , Paclitaxel/farmacologia , Tamoxifeno/farmacologia
17.
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
18.
Nanoscale ; 11(30): 14226-14236, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31317161

RESUMO

In eukaryotic cells, each process, in which DNA is involved, should take place in the context of a chromatin structure. DNA double-strand breaks (DSBs) are one of the most deleterious lesions often leading to chromosomal rearrangement. In response to environmental stresses, cells have developed repair mechanisms to eliminate the DSBs. Upon DSB induction, several factors play roles in chromatin relaxation by catalysing the appropriate histone posttranslational modification (PTM) steps, therefore promoting the access of the repair factors to the DSBs. Among these PTMs, the phosphorylation of the histone variant H2AX at its Ser139 residue (also known as γH2AX) could be observed at the break sites. The structure of a DNA double-strand break induced repair focus has to be organized during the repair as it contributes to the accessibility of specific repair proteins to the damaged site. Our aim was to develop a quantitative approach to analyse the morphology of single repair foci by super-resolution dSTORM microscopy to gain insight into chromatin organization in DNA repair. We have established a specific dSTORM measurement process by developing a new analytical algorithm for gaining quantitative information about chromatin morphology and repair foci topology at an individual γH2AX enriched repair focus. Using this method we quantified single repair foci to show the distribution of γH2AX. The image of individual γH2AX referred to as the Single target Molecule response scatter Plot (SMPlot) was obtained by using high lateral resolution dSTORM images. Determination of the average localization numbers in an SMPlot was one of the key steps of quantitative dSTORM. A repair focus is made up of nanofoci. Such a substructure of repair foci can only be resolved and detected with super-resolution microscopy. Determination of the number of γH2AXs in the nanofoci was another key step of quantitative dSTORM. Additionally, based on our new analysis method, we were able to show the number of nucleosomes in each nanofocus that could allow us to define the possible chromatin structure and the nucleosome density around the break sites. This method is one of the first demonstrations of a single-cell based quantitative measurement of a discrete repair focus, which could provide new opportunities to categorize the spatial organization of nanofoci by parametric determination of topological similarity.


Assuntos
Quebras de DNA de Cadeia Dupla , Reparo do DNA , Algoritmos , Linhagem Celular Tumoral , Núcleo Celular/genética , Núcleo Celular/metabolismo , Cromatina/química , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Histonas/genética , Histonas/metabolismo , Humanos , Microscopia/métodos , Tamoxifeno/análogos & derivados , Tamoxifeno/farmacologia
19.
Molecules ; 24(14)2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31319579

RESUMO

In this study, we tested the potential cardioprotective effects of the phytoalexin resveratrol (Rsv) on primary adult rat cardiac fibroblasts (CF), myofibroblasts (MF) and cardiomyocytes. Adult rat CF and cardiomyocytes were isolated from male 10-week old Sprague-Dawley rats, cultured for either 24 h (cardiomyocytes) or 48 h (CF) before treatments. To isolate MF, CF were trypsinized after 48 h in culture, seeded in fresh plates and cultured for 24 h prior to treatment. All three cells were then treated for a further 24 h with a range of Rsv doses. In CF and MF, cell proliferation, viability, apoptosis assays were performed with or without Rsv treatment for 24 h. In cardiomyocytes, cell viability and apoptosis assay were performed 24 h after treatment. In separate experiments, CF was pre-incubated with estrogen, tamoxifen and fulvestrant for 30 min prior to Rsv treatment. Rsv treatment decreased proliferation of both fibroblasts and myofibroblasts. Rsv treatment also increased the proportion of dead CF and MF in a dose dependent manner. However, treatment with Rsv did not induce cell death in adult cardiomyocytes. There was an increase in the percentage of cells with condensed nuclei with Rsv treatment in both CF and MF, but not in cardiomyocytes. Treatment with estrogen, tamoxifen and fulvestrant alone or in combination with Rsv did not have any additional effects on CF survival. Our results demonstrate that treatment with Rsv can inhibit cell proliferation and induce cell death in rat CF and MF, while not affecting cardiomyocyte survival. We also demonstrated that the induction of cell death in CF with Rsv treatment was independent of estrogen receptor alpha (ERα) signaling.


Assuntos
Proliferação de Células/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Miofibroblastos/efeitos dos fármacos , Resveratrol/farmacologia , Animais , Apoptose/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Receptor alfa de Estrogênio/genética , Humanos , Ratos , Sesquiterpenos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Estilbenos/química , Tamoxifeno/farmacologia
20.
Oncology ; 97(3): 180-188, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31330520

RESUMO

BACKGROUND: Hormone receptor-positive breast cancer accounts for nearly two-thirds of breast cancer cases; it ultimately acquires resistance during endocrine treatment and becomes more aggressive. This study evaluated the role of developmental endothelial locus (Del)-1 in tamoxifen-resistant (TAM-R) breast cancer. METHODS: Del-1 expression in recurrent TAM-R breast cancer tissue was evaluated and compared to that in the original tumor tissue from the same patients. Del-1 expression was also evaluated in TAM-R cells by quantitative real-time PCR, western blotting, and enzyme-linked immunosorbent assay. The effects of Del-1 knockdown on the proliferation, migration, and invasion of TAM-R cells was assessed with wound-healing and Matrigel transwell assays. RESULTS: Del-1 was more highly expressed in recurrent breast cancer as compared to the original tumor tissues before initiation of endocrine treatment. Del-1 mRNA was upregulated in TAM-R and small interfering RNA-mediated knockdown of Del-1 suppressed the migration and proliferation of TAM-R cells while partly restoring TAM sensitivity. And the TAM resistance was recovered by knockdown of Del-1. CONCLUSIONS: TAM-R breast cancer is characterized by Del-1 overexpression and tumor progression can be inhibited by Del-1 depletion, which restores TAM sensitivity. Thus, therapeutic strategies that target Del-1 may be effective for the treatment of hormone-resistant breast cancer.


Assuntos
Antineoplásicos Hormonais/farmacologia , Neoplasias da Mama/genética , Proteínas de Transporte/genética , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Tamoxifeno/farmacologia , Neoplasias da Mama/metabolismo , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Feminino , Técnicas de Silenciamento de Genes , Humanos , Interferência de RNA , RNA Interferente Pequeno
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