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1.
Cell Transplant ; 30: 963689721991477, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33522308

RESUMO

TRANSLATIONAL RELEVANCE: No prophylactic treatments for COVID-19 have been clearly proven and found. In this pandemic context, cancer patients constitute a particularly fragile population that would benefit the best from such treatments, a present unmet need. TMPRSS2 is essential for COVID-19 replication cycle and it is under androgen control. Estrogen and androgen receptor dependent cues converge on TMPRSS2 regulation through different mechanisms of action that can be blocked by the use of hormonal therapies. We believe that there is enough body of evidence to foresee a prophylactic use of hormonal therapies against COVID-19 and this hypothesis can be easily tested on cohorts of breast and prostate cancer patients who follow those regimens. In case of pandemic, if the protective effect of hormonal therapies will be proven on cancer patients, the use of specific hormonal therapies could be extended to other oncological groups and to healthy individuals to decrease the overall risk of infection by SARS-CoV-2.Given the COVID-19 coronavirus emergency, a special focus is needed on the impact of this rapidly spreading viral infection on cancer patients. Androgen receptor (AR) signaling in the transmembrane protease serine 2 (TMPRSS2) regulation is emerging as an important determinant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) susceptibility. In our study, we analyzed AR and TMPRSS2 expression in 17,352 normal and 9,556 cancer tissues from public repositories and stratified data according to sex and age. The emerging picture is that some patient groups may be particularly susceptible to SARS-CoV-2 infection and may benefit from antiandrogen- or tamoxifen-based therapies. These findings are relevant to choose proper treatments in order to protect cancer patients from concomitant SARS-CoV-2 contagion and related symptoms and put forward the idea that hormonal therapies could be used as prophylactic agents against COVID-19.


Assuntos
Antagonistas de Receptores de Andrógenos/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/complicações , Antagonistas de Estrogênios/uso terapêutico , Neoplasias da Próstata/complicações , Tamoxifeno/uso terapêutico , Antagonistas de Receptores de Andrógenos/farmacologia , Antineoplásicos Hormonais/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , /metabolismo , Descoberta de Drogas , Antagonistas de Estrogênios/farmacologia , Feminino , Humanos , Masculino , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/análise , Receptores Androgênicos/metabolismo , Serina Endopeptidases/análise , Serina Endopeptidases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tamoxifeno/farmacologia
2.
Mol Biol (Mosk) ; 55(1): 118-125, 2021.
Artigo em Russo | MEDLINE | ID: mdl-33566031

RESUMO

Crosstalk between the estrogen receptors and the receptor tyrosine kinases, including vascular endothelial growth factor receptor type II (VEGFR2), is a key mechanism in breast cancer resistance to antiestrogen therapy with tamoxifen. A high level of VEGFR2 expression in a tumor serves as a marker of tamoxifen resistance. The tamoxifen efficacy prognostic value of functional polymorphisms in the VEGFR2/KDR gene has not been established. Using qRT-PCR, we detected the rs2071559 and the rs2305948 variants and the levels of KDR gene expression in 122 breast tumor tissue samples from cohorts of patients with progression (distant metastases or relapse) and patients with no progression during tamoxifen therapy. The expression levels of VEGFR2 protein were analyzed by immunohistochemistry. The frequency of heterozygous and mutant genotypes of the rs2305948 SNP was significantly higher in patients without progression than in the cohort with progression. KDR rs2305948 was associated with high survival rates in breast cancer patients. A correlation between the mRNA of the ESR1 and KDR genes in patients without progression was detected. The results indicate the prognostic value of rs2305948 and its potential contribution to the tumor phenotype sensitive to tamoxifen.


Assuntos
Neoplasias da Mama , Fator A de Crescimento do Endotélio Vascular , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Estrogênios , Humanos , Tamoxifeno/uso terapêutico , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética
3.
Lancet Oncol ; 22(2): 212-222, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33460574

RESUMO

BACKGROUND: Palbociclib added to endocrine therapy improves progression-free survival in hormone-receptor-positive, HER2-negative, metastatic breast cancer. The PALLAS trial aimed to investigate whether the addition of 2 years of palbociclib to adjuvant endocrine therapy improves invasive disease-free survival over endocrine therapy alone in patients with hormone-receptor-positive, HER2-negative, early-stage breast cancer. METHODS: PALLAS is an ongoing multicentre, open-label, randomised, phase 3 study that enrolled patients at 406 cancer centres in 21 countries worldwide with stage II-III histologically confirmed hormone-receptor-positive, HER2-negative breast cancer, within 12 months of initial diagnosis. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance score of 0 or 1. Patients were randomly assigned (1:1) in permuted blocks of random size (4 or 6), stratified by anatomic stage, previous chemotherapy, age, and geographical region, by use of central telephone-based and web-based interactive response technology, to receive either 2 years of palbociclib (125 mg orally once daily on days 1-21 of a 28-day cycle) with ongoing standard provider or patient-choice adjuvant endocrine therapy (tamoxifen or aromatase inhibitor, with or without concurrent luteinising hormone-releasing hormone agonist), or endocrine therapy alone, without masking. The primary endpoint of the study was invasive disease-free survival in the intention-to-treat population. Safety was assessed in all randomly assigned patients who started palbociclib or endocrine therapy. This report presents results from the second pre-planned interim analysis triggered on Jan 9, 2020, when 67% of the total number of expected invasive disease-free survival events had been observed. The trial is registered with ClinicalTrials.gov (NCT02513394) and EudraCT (2014-005181-30). FINDINGS: Between Sept 1, 2015, and Nov 30, 2018, 5760 patients were randomly assigned to receive palbociclib plus endocrine therapy (n=2883) or endocrine therapy alone (n=2877). At the time of the planned second interim analysis, at a median follow-up of 23·7 months (IQR 16·9-29·2), 170 of 2883 patients assigned to palbociclib plus endocrine therapy and 181 of 2877 assigned to endocrine therapy alone had invasive disease-free survival events. 3-year invasive disease-free survival was 88·2% (95% CI 85·2-90·6) for palbociclib plus endocrine therapy and 88·5% (85·8-90·7) for endocrine therapy alone (hazard ratio 0·93 [95% CI 0·76-1·15]; log-rank p=0·51). As the test statistic comparing invasive disease-free survival between groups crossed the prespecified futility boundary, the independent data monitoring committee recommended discontinuation of palbociclib in patients still receiving palbociclib and endocrine therapy. The most common grade 3-4 adverse events were neutropenia (1742 [61·3%] of 2840 patients on palbociclib and endocrine therapy vs 11 [0·3%] of 2903 on endocrine therapy alone), leucopenia (857 [30·2%] vs three [0·1%]), and fatigue (60 [2·1%] vs ten [0·3%]). Serious adverse events occurred in 351 (12·4%) of 2840 patients on palbociclib plus endocrine therapy versus 220 (7·6%) of 2903 patients on endocrine therapy alone. There were no treatment-related deaths. INTERPRETATION: At the planned second interim analysis, addition of 2 years of adjuvant palbociclib to adjuvant endocrine therapy did not improve invasive disease-free survival compared with adjuvant endocrine therapy alone. On the basis of these findings, this regimen cannot be recommended in the adjuvant setting. Long-term follow-up of the PALLAS population and correlative studies are ongoing. FUNDING: Pfizer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Inibidores da Aromatase/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Piperazinas/administração & dosagem , Piridinas/administração & dosagem , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Piperazinas/efeitos adversos , Modelos de Riscos Proporcionais , Piridinas/efeitos adversos , Receptor ErbB-2/genética , Receptores Estrogênicos/genética , Tamoxifeno/administração & dosagem
4.
Cochrane Database Syst Rev ; 12: CD007245, 2020 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-33348436

RESUMO

BACKGROUND: Adjuvant tamoxifen reduces the risk of breast cancer recurrence in women with oestrogen receptor-positive breast cancer. Tamoxifen also increases the risk of postmenopausal bleeding, endometrial polyps, hyperplasia, and endometrial cancer. The levonorgestrel-releasing intrauterine system (LNG-IUS) causes profound endometrial suppression. This systematic review considered the evidence that the LNG-IUS prevents the development of endometrial pathology in women taking tamoxifen as adjuvant endocrine therapy for breast cancer. OBJECTIVES: To determine the effectiveness and safety of the levonorgestrel intrauterine system (LNG-IUS) in pre- and postmenopausal women taking adjuvant tamoxifen following breast cancer for the outcomes of endometrial and uterine pathology including abnormal vaginal bleeding or spotting, and secondary breast cancer events. SEARCH METHODS: We searched the following databases on 29 June 2020; The Cochrane Gynaecology and Fertility Group specialised register, Cochrane Central Register of Controlled Trials, MEDLINE, Embase, PsycINFO and Cumulative Index to Nursing and Allied Health Literature. We searched the Cochrane Breast Cancer Group specialised register on 4 March 2020. We also searched two trials registers, checked references for relevant trials and contacted study authors and experts in the field to identify additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of women with breast cancer on adjuvant tamoxifen that compared the effectiveness of the LNG-IUS with endometrial surveillance versus endometrial surveillance alone on the incidence of endometrial pathology. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. The primary outcome measure was endometrial pathology (including polyps, endometrial hyperplasia, or endometrial cancer), diagnosed at hysteroscopy or endometrial biopsy. Secondary outcome measures included fibroids, abnormal vaginal bleeding or spotting, breast cancer recurrence, and breast cancer-related deaths. We rated the overall certainty of evidence using GRADE methods. MAIN RESULTS: We included four RCTs (543 women analysed) in this review. We judged the certainty of the evidence to be moderate for all of the outcomes, due to imprecision (i.e. limited sample sizes and low event rates). In the included studies, the active treatment arm was the 20 µg/day LNG-IUS plus endometrial surveillance; the control arm was endometrial surveillance alone. In tamoxifen users, the LNG-IUS probably reduces the incidence of endometrial polyps compared to the control group over both a 12-month period (Peto odds ratio (OR) 0.22, 95% confidence interval (CI) 0.08 to 0.64, I² = 0%; 2 RCTs, n = 212; moderate-certainty evidence) and over a long-term follow-up period (24 to 60 months) (Peto OR 0.22, 95% CI 0.13 to 0.39; I² = 0%; 4 RCTs, n = 417; moderate-certainty evidence). For long-term follow-up, this suggests that if the incidence of endometrial polyps following endometrial surveillance alone is assumed to be 23.5%, the incidence following LNG-IUS with endometrial surveillance would be between 3.8% and 10.7%.  The LNG-IUS probably slightly reduces the incidence of endometrial hyperplasia compared with controls over a long-term follow-up period (24 to 60 months) (Peto OR 0.13, 95% CI 0.03 to 0.67; I² = 0%; 4 RCTs, n = 417; moderate-certainty evidence). This suggests that if the chance of endometrial hyperplasia following endometrial surveillance alone is assumed to be 2.8%, the chance following LNG-IUS with endometrial surveillance would be between 0.1% and 1.9%. However, it should be noted that there were only six cases of endometrial hyperplasia. There was insufficient evidence to reach a conclusion regarding the incidence of endometrial cancer in tamoxifen users, as no studies reported cases of endometrial cancer. At 12 months of follow-up, the LNG-IUS probably increases abnormal vaginal bleeding or spotting compared to the control group (Peto OR 7.26, 95% CI 3.37 to 15.66; I² = 0%; 3 RCTs, n = 376; moderate-certainty evidence). This suggests that if the chance of abnormal vaginal bleeding or spotting following endometrial surveillance alone is assumed to be 1.7%, the chance following LNG-IUS with endometrial surveillance would be between 5.6% and 21.5%. By 24 months of follow-up, abnormal vaginal bleeding or spotting occurs less frequently than at 12 months of follow-up, but is still more common in the LNG-IUS group than the control group (Peto OR 2.72, 95% CI 1.04 to 7.10; I² = 0%; 2 RCTs, n = 233; moderate-certainty evidence). This suggests that if the chance of abnormal vaginal bleeding or spotting following endometrial surveillance alone is assumed to be 4.2%, the chance following LNG-IUS with endometrial surveillance would be between 4.4% and 23.9%. By 60 months of follow-up, there were no cases of abnormal vaginal bleeding or spotting in either group. The numbers of events for the following outcomes were low: fibroids (n = 13), breast cancer recurrence (n = 18), and breast cancer-related deaths (n = 16). As a result, there is probably little or no difference in these outcomes between the LNG-IUS treatment group and the control group.  AUTHORS' CONCLUSIONS: The LNG-IUS probably slightly reduces the incidence of benign endometrial polyps and endometrial hyperplasia in women with breast cancer taking tamoxifen. At 12 and 24 months of follow-up, the LNG-IUS probably increases abnormal vaginal bleeding or spotting among women in the treatment group compared to those in the control. Data were lacking on whether the LNG-IUS prevents endometrial cancer in these women. There is no clear evidence from the available RCTs that the LNG-IUS affects the risk of breast cancer recurrence or breast cancer-related deaths. Larger studies are necessary to assess the effects of the LNG-IUS on the incidence of endometrial cancer, and to determine whether the LNG-IUS might have an impact on the risk of secondary breast cancer events.


Assuntos
Neoplasias da Mama/prevenção & controle , Hiperplasia Endometrial/prevenção & controle , Neoplasias do Endométrio/prevenção & controle , Dispositivos Intrauterinos Medicados , Levanogestrel/administração & dosagem , Recidiva Local de Neoplasia/prevenção & controle , Adenocarcinoma/induzido quimicamente , Adenocarcinoma/prevenção & controle , Antineoplásicos Hormonais/efeitos adversos , Neoplasias da Mama/química , Neoplasias da Mama/mortalidade , Quimioterapia Adjuvante , Intervalos de Confiança , Anticoncepcionais Femininos/administração & dosagem , Hiperplasia Endometrial/induzido quimicamente , Hiperplasia Endometrial/epidemiologia , Neoplasias do Endométrio/induzido quimicamente , Neoplasias do Endométrio/epidemiologia , Feminino , Humanos , Levanogestrel/efeitos adversos , Recidiva Local de Neoplasia/mortalidade , Pólipos/induzido quimicamente , Pólipos/epidemiologia , Pólipos/prevenção & controle , Ensaios Clínicos Controlados Aleatórios como Assunto , Tamoxifeno/efeitos adversos , Hemorragia Uterina/induzido quimicamente , Hemorragia Uterina/epidemiologia , Útero/efeitos dos fármacos
6.
Zhonghua Nan Ke Xue ; 26(1): 74-77, 2020 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-33345481

RESUMO

Objective: To study the effect of the traditional Chinese therapy of tonifying the kidney and invigorating blood circulation (TKIB) on male infertility. METHODS: Forty-two infertile males with abnormal DNA fragmentation index (DFI) were randomly allocated into a TKIB (n = 22) and a control group (n = 20), the former treated by TKIB with an oral Chinese medicinal prescription while the latter with oral tamoxifen tablets and vitamin E capsules, both for 3 months. Before and after treatment, we obtained the semen parameters and sperm DFI from the patients and followed them up for the outcomes of natural pregnancy. RESULTS: Compared with the baseline, the patients in both the TKIB and control groups showed significant increases after medication in sperm concentration (ï¼»36.82 ± 29.16ï¼½ and ï¼»34.56 ± 37.03ï¼½ vs ï¼»50.00 ± 39.16ï¼½ and ï¼»40.72 ± 47.37ï¼½ ×106/ml, P<0.05), the percentage of progressively motile sperm (PMS) (ï¼»20.62 ± 9.10ï¼½% and ï¼»21.25 ± 9.11ï¼½% vs ï¼»36.82 ± 13.45ï¼½% and ï¼»26.18 ± 10.60ï¼½%, P<0.05) and the percentage of morphologically normal sperm (MNS) (ï¼»1.28 ± 1.00ï¼½% and ï¼»1.48 ± 0.91ï¼½% vs ï¼»3.44 ± 1.33ï¼½% and ï¼»2.57 ± 1.32ï¼½%, P<0.05), but remarkably decreased sperm DFI (ï¼»29.07 ± 11.52ï¼½% and ï¼»24.43 ± 8.46ï¼½% vs ï¼»15.51 ± 11.31ï¼½% and ï¼»18.53 ± 10.44ï¼½%, P<0.05). The patients of the TKIB group exhibited an even higher total sperm motility and percentages of PMS and MNS than those of the control group (P<0.05) but no statistically significant difference from the latter in sperm concentration or DFI (P>0.05). Besides, the former achieved higher rates of natural pregnancy (18.2%) and live birth (18.2%) than the controls (15% and 10%) though neither with statistically significant difference (P>0.05). CONCLUSIONS: The traditional Chinese therapy of tonifying the kidney and invigorating blood circulation can reduce sperm DNA damage and improve the outcomes of natural pregnancy in infertile men.


Assuntos
Dano ao DNA , Infertilidade Masculina , Medicina Tradicional Chinesa , Motilidade Espermática , Circulação Sanguínea , Fragmentação do DNA , Feminino , Humanos , Infertilidade Masculina/tratamento farmacológico , Rim , Masculino , Gravidez , Taxa de Gravidez , Contagem de Espermatozoides , Espermatozoides , Tamoxifeno
7.
Nat Commun ; 11(1): 5513, 2020 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-33139730

RESUMO

Cyclin D1 is one of the most important oncoproteins that drives cancer cell proliferation and associates with tamoxifen resistance in breast cancer. Here, we identify a lncRNA, DILA1, which interacts with Cyclin D1 and is overexpressed in tamoxifen-resistant breast cancer cells. Mechanistically, DILA1 inhibits the phosphorylation of Cyclin D1 at Thr286 by directly interacting with Thr286 and blocking its subsequent degradation, leading to overexpressed Cyclin D1 protein in breast cancer. Knocking down DILA1 decreases Cyclin D1 protein expression, inhibits cancer cell growth and restores tamoxifen sensitivity both in vitro and in vivo. High expression of DILA1 is associated with overexpressed Cyclin D1 protein and poor prognosis in breast cancer patients who received tamoxifen treatment. This study shows the previously unappreciated importance of post-translational dysregulation of Cyclin D1 contributing to tamoxifen resistance in breast cancer. Moreover, it reveals the novel mechanism of DILA1 in regulating Cyclin D1 protein stability and suggests DILA1 is a specific therapeutic target to downregulate Cyclin D1 protein and reverse tamoxifen resistance in treating breast cancer.


Assuntos
Antineoplásicos Hormonais/farmacologia , Neoplasias da Mama/tratamento farmacológico , Ciclina D1/genética , RNA Longo não Codificante/metabolismo , Tamoxifeno/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Pessoa de Meia-Idade , Prognóstico , Processamento de Proteína Pós-Traducional/genética , Estabilidade Proteica , Proteólise , RNA Longo não Codificante/genética , Tamoxifeno/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto Jovem
8.
Nat Commun ; 11(1): 5356, 2020 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-33097716

RESUMO

Krabbe disease (KD) is caused by a deficiency of galactosylceramidase (GALC), which induces demyelination and neurodegeneration due to accumulation of cytotoxic psychosine. Hematopoietic stem cell transplantation (HSCT) improves clinical outcomes in KD patients only if delivered pre-symptomatically. Here, we hypothesize that the restricted temporal efficacy of HSCT reflects a requirement for GALC in early brain development. Using a novel Galc floxed allele, we induce ubiquitous GALC ablation (Galc-iKO) at various postnatal timepoints and identify a critical period of vulnerability to GALC ablation between P4-6 in mice. Early Galc-iKO induction causes a worse KD phenotype, higher psychosine levels in the rodent brainstem and spinal cord, and a significantly shorter life-span of the mice. Intriguingly, GALC expression peaks during this critical developmental period in mice. Further analysis of this mouse model reveals a cell autonomous role for GALC in the development and maturation of immature T-box-brain-1 positive brainstem neurons. These data identify a perinatal developmental period, in which neuronal GALC expression influences brainstem development that is critical for KD pathogenesis.


Assuntos
Tronco Encefálico/enzimologia , Tronco Encefálico/crescimento & desenvolvimento , Tronco Encefálico/metabolismo , Galactosilceramidase/genética , Galactosilceramidase/metabolismo , Leucodistrofia de Células Globoides/genética , Leucodistrofia de Células Globoides/metabolismo , Animais , Tronco Encefálico/embriologia , Modelos Animais de Doenças , Regulação da Expressão Gênica no Desenvolvimento , Transplante de Células-Tronco Hematopoéticas , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/metabolismo , Fenótipo , Psicosina/metabolismo , Tamoxifeno , Transcriptoma
9.
Maturitas ; 141: 71-81, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33036706

RESUMO

BACKGROUND: Side-effects of hormone therapy can impair the physical health of breast cancer survivors. Exercise has been clearly shown to improve the quality of life of breast cancer survivors. Less is known about the effects of exercise on physical outcomes for breast cancer survivors receiving hormone therapy. OBJECTIVE: To investigate the effects of exercise on physical outcomes of breast cancer survivors receiving hormone therapy. METHODS: Five electronic databases were searched by two authors using the terms "Breast Neoplasms" [MeSH] and "Tamoxifen" [MeSH] and "Aromatase Inhibitors" [MeSH] and "Exercise" [MeSH]. Randomized and non-randomized clinical trials were included. Risk of bias was assessed by the Cochrane Collaboration tool and ROBINS-I, and the quality of evidence was evaluated using GRADE. Pooled effects were reported as standardized mean differences (SMDs) and 95 % confidence intervals (CIs) using a random effects model. RESULTS: Eleven studies were included in the meta-analysis. Two hundred and fourteen breast cancer survivors receiving hormone therapy, tamoxifen, or aromatase inhibitors participated in interventions based on aerobic plus resistance exercise or walking activity. The physical outcomes reported in the articles were: cardiorespiratory fitness, pain, bone mineral density, grip strength, and body fat percentage. Exercise effects were found only for cardiorespiratory fitness (SMD = 0.37; 95 % CI: 0.11; 0.63; I2 = 93 %) and pain (SMD = -0.55; IC95 % -1.11; -0.00; I2 = 80 %), with low quality of evidence. No effects were observed for the other variables. CONCLUSIONS: Aerobic plus resistance exercise had positive effects on cardiorespiratory fitness and pain in breast cancer survivors receiving hormone therapy. However, high-quality randomized clinical trials are required to confirm this finding.


Assuntos
Antineoplásicos Hormonais/efeitos adversos , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/reabilitação , Sobreviventes de Câncer , Exercício Físico , Tamoxifeno/efeitos adversos , Densidade Óssea , Neoplasias da Mama/tratamento farmacológico , Terapia por Exercício , Feminino , Humanos , Qualidade de Vida , Sobreviventes , Caminhada
10.
Chem Biol Interact ; 331: 109274, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33007288

RESUMO

BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer mortality worldwide. Mutations in the adenomatous polyposis coli (APC) gene are pivotal in colorectal tumorigenesis. Recently, we demonstrated that aldehyde dehydrogenase 1B1 (ALDH1B1) knockdown dramatically reduced colon tumor growth in a mouse xenograft model. The purpose of the present preliminary study is to examine the effect of loss of ALDH1B1 in CRC development in an inducible colon-specific Apc mouse model. METHODS: ApcW/FCdx2ERT2-Cre mice develop uni-allelic inactivation of Apc specifically in colon epithelial cells following tamoxifen treatment. Aldh1b1-/- KO mice were crossed with ApcW/FCdx2ERT2-Cre mice. Six-month-old male ApcW/FCdx2ERT2-Cre/Aldh1b1-/-, and ApcW/FCdx2ERT2-Cre/Aldh1b1+/+ mice were treated with tamoxifen (50 mg/kg, i.p.) for three consecutive days. ApcW/F/Aldh1b1-/- and ApcW/F/Aldh1b1+/+ mice were treated with corn oil (i.e., tamoxifen vehicle control) for three consecutive days. Eighteen days later, mice were sacrificed and their colons examined microscopically, macroscopically and histologically for the presence of adenoma. RESULTS: All ApcW/FCdx2ERT2-Cre/Aldh1b1+/+ and ApcW/FCdx2ERT2-Cre/Aldh1b1-/- mice treated with tamoxifen developed colorectal adenoma. The ApcW/FCdx2ERT2-Cre/Aldh1b1-/- mice showed a significant decrease in the total volume of all ileal and colonic adenomas, and decreased incidence of large colonic adenoma compared to ApcW/FCdx2ERT2-Cre/Aldh1b1+/+ mice. Immunohistochemical analysis of p53 and ß-catenin showed a trend toward decreased expression score in colonic adenomas of ApcW/FCdx2ERT2-Cre/Aldh1b1-/- mice. CONCLUSION: The present preliminary study suggests that deletion of ALDH1B1 may protect against the full development of colorectal cancer. Further mechanistic studies are required to elucidate how ALDH1B1 contributes for colorectal cancer.


Assuntos
Polipose Adenomatosa do Colo/patologia , Aldeído-Desidrogenase Mitocondrial/metabolismo , Neoplasias Colorretais/patologia , Polipose Adenomatosa do Colo/metabolismo , /genética , Aldeído-Desidrogenase Mitocondrial/deficiência , Aldeído-Desidrogenase Mitocondrial/genética , Animais , Neoplasias Colorretais/metabolismo , Modelos Animais de Doenças , Genótipo , Intestino Grosso/metabolismo , Intestino Grosso/patologia , Intestino Delgado/metabolismo , Intestino Delgado/patologia , Camundongos , Camundongos Knockout , Tamoxifeno , Proteína Supressora de Tumor p53/metabolismo , beta Catenina/metabolismo
11.
Crit Rev Oncol Hematol ; 156: 103114, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33045493

RESUMO

BACKGROUND: Extended endocrine therapy (EET) with aromatase inhibitors (AIs) therapy can further reduce the risk of recurrence in breast cancer patients. But the conclusion that whether EET with AIs increases the risk of some side effects compared with nonextended endocrine therapy (NEET) is still controversial and not exhaustive. METHODS: We searched for Randomized controlled trials (RCT) trials published in EMBASE and PubMed between March 2008 and December 2019. Studies comparing the side effects of adjuvant EET with those of NEET were included. The objective was to determine whether EET with AIs increases the risk of side effects compared with NEET. RESULTS: Overall, 11 trials comprising 24,187 participants were identified. EET with AIs increased the risk of cardiotoxicity [odds ratio (OR) 1.19, 95 % confidence interval (CI) 1.04-1.36; P < 0.05; 438 vs 423], bone pain (OR 1.18, 95 % CI 1.02-1.36; P < 0.05; 446 vs 404), osteoporosis (OR 1.53, 95 % CI 1.35-1.72; P < 0.05; 866 vs 641), fractures (OR 1.33, 95 % CI 1.18-1.50; P < 0.05; 596 vs 438), arthralgia (OR 1.27, 95 % CI 1.19-1.36; P < 0.05; 2404 vs 2060), myalgia (OR 1.29, 95 % CI 1.16-1.43; P < 0.05; 960 vs 776), and hot flashes (OR 1.40, 95 % CI 1.15-1.69; P < 0.05; 2418 vs 2174) and was associated with opposite risk of vaginal bleeding (OR 0.74, 95 % CI 0.59-0.92; P < 0.05; 148 vs 197). However, the extended therapy did not increase the risk of hypertension (OR 1.03, 95 % CI 0.80-1.33; P = 0.80; 364 vs 353), hypercholesterolemia (OR 1.03, 95 % CI 0.91-1.16; P = 0.62; 643 vs 627), vaginal dryness (OR 1.19, 95 % CI 1.00-1.42; P = 0.05; 294 vs 257), fatigue (OR 1.20, 95 % CI 0.96-1.50; P = 0.12; 1501 vs 1462), dizziness (OR 1.04, 95 % CI 0.92-1.17; P = 0.55; 614 vs 595), headaches (OR 1.06, 95 % CI 0.95-1.18; P = 0.30; 885 vs 848), constipation (OR 0.91, 95 % CI 0.79-1.04; P = 0.15; 480 vs 522), nausea (OR 1.83, 95 % CI 0.49-6.83; P =0.37; 340 vs 325), and dyspnea (OR 0.96, 95 % CI 0.82-1.13; P = 0.64; 340 vs 351). The risk of grade ≥ 3 hot flashes increased following extended endocrine therapy (OR 2.01, 95 % CI 1.23-3.29; P < 0.05; 47 vs 23). We observed no evidence for a difference in the risk of grade ≥3 fatigue, arthralgia, myalgia, bone pain, osteoporosis, fractures, hypertension, and headache between both endocrine therapies. Secondary outcomes shows that after receive EET with AIs, patients can benefit from the control of the local recurrence, distant recurrence, contralateral breast cancer, and second cancers. CONCLUSIONS: Compared with NEET, EET with AIs significantly increased the risk of cardiotoxicity, bone pain, osteoporosis, fractures, hot flashes, arthralgia, myalgia, and grade ≥3 hot flashes, and EET with AIs can reduced the risks of local recurrence, distant recurrence, contralateral breast cancer, and second cancers. These findings offer an important guide for clinicians and patients.


Assuntos
Neoplasias da Mama , Segunda Neoplasia Primária , Antineoplásicos Hormonais/efeitos adversos , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Quimioterapia Adjuvante , Feminino , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Pós-Menopausa , Tamoxifeno/uso terapêutico
12.
Bull Cancer ; 107(11): 1171-1185, 2020 Nov.
Artigo em Francês | MEDLINE | ID: mdl-32988609

RESUMO

Breast cancer is the most frequently diagnosed cancer in women and the first cause of cancer death in France. Among the different subtypes of breast cancer, the predominant form is characterized by positive hormone receptors (more than 70% of breast cancers). Hormone therapy thus plays a key role in the strategy of management of these cancers both in adjuvant and metastatic situations. The two types of adjuvant hormone therapy used are selective estrogen receptor modulators and aromatase inhibitors. Fulvestrant, an anti-estrogen, is used alone or in combination with other molecules in metastatic situations. Hot flashes are one of the symptoms most frequently reported by patients under hormone therapy. Hormone replacement therapy, which is currently the most effective treatment for hot flashes, is contraindicated in patients with a personal history of breast cancer. Various therapeutic classes of drugs have been tested in this indication but without real efficacy in the various studies carried out to date, and moreover associated with non-negligible side effects. The recent discovery of the implication of the kisspeptin system located at the hypothalamic level in the mechanism of genesis of hot flashes opens the way to possible new symptomatic treatments for hot flashes. Neurokinin 3 receptor antagonists have shown encouraging preliminary results in postmenopausal cancer-free patients and could be considered in patients in hormonal therapy for breast cancer. Broader additional studies are needed to confirm these initial results.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/química , Neoplasias da Mama/tratamento farmacológico , Fogachos/etiologia , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Contraindicações de Medicamentos , Terapia de Reposição de Estrogênios/efeitos adversos , Feminino , Fulvestranto/uso terapêutico , Humanos , Kisspeptinas/fisiologia , Ovário/efeitos dos fármacos , Ovário/cirurgia , Receptores da Neurocinina-3/antagonistas & inibidores , Moduladores Seletivos de Receptor Estrogênico/administração & dosagem , Tamoxifeno/administração & dosagem , Tamoxifeno/uso terapêutico
13.
Proc Natl Acad Sci U S A ; 117(39): 24205-24212, 2020 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-32934143

RESUMO

The sonic hedgehog subtype of medulloblastoma (SHH MB) is associated with treatment failure and poor outcome. Current strategies utilizing whole brain radiation therapy result in deleterious off-target effects on the normal developing childhood brain. Most conventional chemotherapies remain limited by ineffective blood-brain barrier (BBB) penetrance. These challenges signify an unmet need for drug carriers that can cross the BBB and deliver drugs to targeted sites with high drug-loading efficiency and long-term stability. We herein leverage the enhanced stability and targeting ability of engineered high-density lipoprotein-mimetic nanoparticles (eHNPs) to cross the BBB and deliver a SHH inhibitor effectively to the cancer stem-like cell population in SHH MB. Our microfluidic technology enabled highly reproducible production of multicomponent eHNPs incorporated with apolipoprotein A1, anti-CD15, and a SHH inhibitor (LDE225). We demonstrate the dual-targeted delivery and enhanced therapeutic effect of eHNP-A1-CD15-LDE225 via scavenger receptor class B type 1 (SR-B1) and CD15 on brain SHH MB cells in vitro, ex vivo, and in vivo. Moreover, we show that eHNP-A1 not only serves as a stable drug carrier, but also has a therapeutic effect itself through SR-B1-mediated intracellular cholesterol depletion in SHH MB cells. Through the facilitated and targeted cellular uptake of drugs and direct therapeutic role of this engineered biomimetic nanocarrier in SHH MB, our multifunctional nanoparticle provides intriguing therapeutic promise as an effective and potent nanomedicine for the treatment of SHH MB.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Cerebelares/tratamento farmacológico , Portadores de Fármacos , Meduloblastoma/tratamento farmacológico , Nanopartículas/química , Animais , Materiais Biomiméticos , Barreira Hematoencefálica , Linhagem Celular Tumoral , HDL-Colesterol , Feminino , Proteínas Hedgehog/antagonistas & inibidores , Humanos , Camundongos Transgênicos , Terapia de Alvo Molecular , Gravidez , Tamoxifeno
14.
PLoS One ; 15(7): e0235232, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32735618

RESUMO

The tamoxifen-dependent Cre/lox system in transgenic mice has become an important research tool across all scientific disciplines for manipulating gene expression in specific cell types. In these mouse models, Cre-recombination is not induced until tamoxifen is administered, which allows researchers to have temporal control of genetic modifications. Interestingly, tamoxifen has been identified as a potential therapy for spinal cord injury (SCI) and traumatic brain injury patients due to its neuroprotective properties. It is also reparative in that it stimulates oligodendrocyte differentiation and remyelination after toxin-induced demyelination. However, it is unknown whether tamoxifen is neuroprotective and neuroreparative when administration is delayed after SCI. To properly interpret data from transgenic mice in which tamoxifen treatment is delayed after SCI, it is necessary to identify the effects of tamoxifen alone on anatomical and functional recovery. In this study, female and male mice received a moderate mid-thoracic spinal cord contusion. Mice were then gavaged with corn oil or a high dose of tamoxifen from 19-22 days post-injury, and sacrificed 42 days post-injury. All mice underwent behavioral testing for the duration of the study, which revealed that tamoxifen treatment did not impact hindlimb motor recovery. Similarly, histological analyses revealed that tamoxifen had no effect on white matter sparing, total axon number, axon sprouting, glial reactivity, cell proliferation, oligodendrocyte number, or myelination, but tamoxifen did decrease the number of neurons in the dorsal and ventral horn. Semi-thin sections confirmed that axon demyelination and remyelination were unaffected by tamoxifen. Sex-specific responses to tamoxifen were also assessed, and there were no significant differences between female and male mice. These data suggest that delayed tamoxifen administration after SCI does not change functional recovery or improve tissue sparing in female or male mice.


Assuntos
Neurônios/efeitos dos fármacos , Remielinização/efeitos dos fármacos , Traumatismos da Medula Espinal/tratamento farmacológico , Tamoxifeno/administração & dosagem , Tempo para o Tratamento , Administração Oral , Animais , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Membro Posterior/inervação , Membro Posterior/fisiologia , Humanos , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Oligodendroglia/efeitos dos fármacos , Recuperação de Função Fisiológica/efeitos dos fármacos , Fatores Sexuais , Corno Dorsal da Medula Espinal/citologia , Corno Dorsal da Medula Espinal/efeitos dos fármacos , Corno Ventral da Medula Espinal/citologia , Corno Ventral da Medula Espinal/efeitos dos fármacos
15.
Nat Commun ; 11(1): 4061, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32792541

RESUMO

Adhesions are fibrotic scars that form between abdominal organs following surgery or infection, and may cause bowel obstruction, chronic pain, or infertility. Our understanding of adhesion biology is limited, which explains the paucity of anti-adhesion treatments. Here we present a systematic analysis of mouse and human adhesion tissues. First, we show that adhesions derive primarily from the visceral peritoneum, consistent with our clinical experience that adhesions form primarily following laparotomy rather than laparoscopy. Second, adhesions are formed by poly-clonal proliferating tissue-resident fibroblasts. Third, using single cell RNA-sequencing, we identify heterogeneity among adhesion fibroblasts, which is more pronounced at early timepoints. Fourth, JUN promotes adhesion formation and results in upregulation of PDGFRA expression. With JUN suppression, adhesion formation is diminished. Our findings support JUN as a therapeutic target to prevent adhesions. An anti-JUN therapy that could be applied intra-operatively to prevent adhesion formation could dramatically improve the lives of surgical patients.


Assuntos
Aderências Teciduais/metabolismo , Aderências Teciduais/patologia , Animais , Benzofenonas/farmacologia , Sistemas CRISPR-Cas , Células Cultivadas , Doxiciclina/farmacologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Imunofluorescência , Gastroenteropatias/metabolismo , Gastroenteropatias/patologia , Humanos , Imuno-Histoquímica , Isoxazóis/farmacologia , Lipossomos/metabolismo , Camundongos , Células NIH 3T3 , Parabiose , RNA Mensageiro/metabolismo , Tamoxifeno/farmacologia
16.
Adv Exp Med Biol ; 1252: 175-179, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32816279

RESUMO

Malignancy may unfortunately present quite early in a woman's life. In the case of breast cancer, rescue of the breast cancer patient's life is the top priority, but after completion of the effective treatment , the question about the ability to accomplish a pregnancy arises. The treatment strategies in breast cancer patients include surgical interventions, chemotherapy , radiotherapy, hormonal therapy and other special types of mainly targeted biologic therapies. Under normal circumstances, surgery for breast cancer does not involve any intervention in the ovaries or the uterus. Thus, even after an extended operation, the anatomic integrity of the gynecological system is guaranteed, and fertility is unaffected.The chemotherapeutic factors that influence fertility are the drug category used, the total dose given, the patient's age at treatment , the drug combination and finally whether targeted therapy is used or not. Alkylating agents are considered to be the most toxic ones. In young breast cancer patients there is a trend to modify regimens to achieve less gonadotoxicity.Evidence regarding tamoxifen, the main used endocrine drug, is scarce and controversial on its direct effect on ovarian reserve. There are not enough studies on the impact of aromatase inhibitors on fertility. Also, HER2-directed agents have not yet demonstrated significant ovarian toxicity and there are scarce data on their effect on fertility.


Assuntos
Neoplasias da Mama/terapia , Preservação da Fertilidade , Fertilidade/fisiologia , Inibidores da Aromatase/efeitos adversos , Feminino , Humanos , Infertilidade Feminina/etiologia , Reserva Ovariana/efeitos dos fármacos , Ovário/efeitos dos fármacos , Ovário/fisiologia , Gravidez , Tamoxifeno/efeitos adversos
19.
Breast Cancer Res ; 22(1): 80, 2020 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-32727562

RESUMO

BACKGROUND: The estrogen receptor (ER)-positive breast cancer represents over 80% of all breast cancer cases. Even though adjuvant hormone therapy with tamoxifen (TMX) is saving lives of patients with ER-positive breast cancer, the acquired resistance to TMX anti-estrogen therapy is the main hurdle for successful TMX therapy. Here we address the mechanism for TMX resistance and explore the ways to eradicate TMX-resistant breast cancer in both in vitro and ex vivo experiments. EXPERIMENTAL DESIGN: To identify compounds able to overcome TMX resistance, we used short-term and long-term viability assays in cancer cells in vitro and in patient samples in 3D ex vivo, analysis of gene expression profiles and cell line pharmacology database, shRNA screen, CRISPR-Cas9 genome editing, real-time PCR, immunofluorescent analysis, western blot, measurement of oxidative stress using flow cytometry, and thioredoxin reductase 1 enzymatic activity. RESULTS: Here, for the first time, we provide an ample evidence that a high level of the detoxifying enzyme SULT1A1 confers resistance to TMX therapy in both in vitro and ex vivo models and correlates with TMX resistance in metastatic samples in relapsed patients. Based on the data from different approaches, we identified three anticancer compounds, RITA (Reactivation of p53 and Induction of Tumor cell Apoptosis), aminoflavone (AF), and oncrasin-1 (ONC-1), whose tumor cell inhibition activity is dependent on SULT1A1. We discovered thioredoxin reductase 1 (TrxR1, encoded by TXNRD1) as a target of bio-activated RITA, AF, and ONC-1. SULT1A1 depletion prevented the inhibition of TrxR1, induction of oxidative stress, DNA damage signaling, and apoptosis triggered by the compounds. Notably, RITA efficiently suppressed TMX-unresponsive patient-derived breast cancer cells ex vivo. CONCLUSION: We have identified a mechanism of resistance to TMX via hyperactivated SULT1A1, which renders selective vulnerability to anticancer compounds RITA, AF, and ONC-1, and provide a rationale for a new combination therapy to overcome TMX resistance in breast cancer patients. Our novel findings may provide a strategy to circumvent TMX resistance and suggest that this approach could be developed further for the benefit of relapsed breast cancer patients.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/farmacologia , Tamoxifeno/farmacologia , Antineoplásicos Hormonais/química , Antineoplásicos Hormonais/farmacologia , Apoptose , Arilsulfotransferase/genética , Arilsulfotransferase/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Tamoxifeno/química , Células Tumorais Cultivadas
20.
Anticancer Res ; 40(8): 4529-4535, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32727783

RESUMO

BACKGROUND/AIM: Although ginseng seed oil (GSO) appears to have various roles in the body, its anti-cancer effect has not been investigated. Tamoxifen is widely used to treat estrogen receptor-positive (ER+) breast cancer but shows adverse effects with drug resistance. This study investigated the effect of GSO in ER+ breast cancer cell growth. MATERIALS AND METHODS: Cell viability assays, western blots and Annexin V staining were conducted to examine cell viability and apoptosis. The synergistic effect of tamoxifen in combination with GSO or oleic acid (OA) was determined. RESULTS: GSO and OA caused apoptosis of MCF-7 ER+ breast cancer cells and had synergistic effects with tamoxifen in inhibiting tamoxifen-resistant MCF-7 (MCF-7TAMR) ER+ breast cancer cell growth. CONCLUSION: GSO may block ER+ breast cancer recurrence in combination with tamoxifen.


Assuntos
Neoplasias da Mama/metabolismo , Ácido Oleico/farmacologia , Panax/química , Óleos Vegetais/farmacologia , Receptores Estrogênicos/metabolismo , Tamoxifeno/farmacologia , Neoplasias da Mama/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Humanos , Células MCF-7 , Óleos Vegetais/química , Sementes/química
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