Assuntos
Androstenos , Niclosamida , Neoplasias de Próstata Resistentes à Castração , Receptores Androgênicos , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores Androgênicos/metabolismo , Receptores Androgênicos/genética , Androstenos/farmacologia , Androstenos/uso terapêutico , Niclosamida/farmacologia , Niclosamida/uso terapêutico , Sinergismo Farmacológico , Antagonistas de Receptores de Andrógenos/farmacologia , Antagonistas de Receptores de Andrógenos/uso terapêuticoRESUMO
Venous thromboembolism is a serious safety concern in women using combined oral contraceptives; ethinyl estradiol (EE) is widely used as an estrogen. Estetrol (E4) is a native estrogen with selective tissue activity and exclusively produced by the fetal liver. This study used a multicenter, randomized, open-label, active-controlled, parallel-group design to evaluate the effects of E4 combined with drospirenone (DRSP) on coagulation and fibrinolysis in Japanese patients with endometriosis. Participants were randomized to receive either E4 15â mg/DRSP 3â mg or EE 20â µg/DRSP 3â mg for 12 weeks. E4/DRSP and EE/DRSP were administered orally once a day in a cyclic regimen, ie, 24-day active use followed by a 4-day hormone-free period, and a flexible extended regimen, respectively, and blood coagulation and fibrinolysis markers were measured. The effect on coagulation and fibrinolysis was considerably less in the E4/DRSP group than in the EE/DRSP group. Major anticoagulant proteins, protein S (free, total) and tissue factor pathway inhibitor (free), were reduced following EE/DRSP treatment. Consequently, thrombin generation determined by the activated protein C sensitivity ratio was increased by approximately 4-fold in the EE/DRSP group than in the E4/DRSP group. Eventually, the fibrinolysis cascade was triggered to compensate for disturbed coagulation, and D-dimer levels were 4.7-fold higher in the EE/DRSP group than in the E4/DRSP group. This study demonstrated that the effect of E4/DRSP on the blood coagulation and fibrinolysis cascades was significantly less than that of EE/DRSP in participants with endometriosis, a disease of women of advanced and reproductive age (jRCT2080225090, https://jrct.niph.go.jp/en-latest-detail/jRCT2080225090).
Assuntos
Androstenos , Coagulação Sanguínea , Endometriose , Estetrol , Fibrinólise , Humanos , Feminino , Fibrinólise/efeitos dos fármacos , Adulto , Coagulação Sanguínea/efeitos dos fármacos , Androstenos/farmacologia , Androstenos/uso terapêutico , Estetrol/farmacologia , Estetrol/uso terapêutico , Endometriose/tratamento farmacológico , Endometriose/sangue , Etinilestradiol/uso terapêutico , Etinilestradiol/farmacologia , Anticoncepcionais Orais Combinados/farmacologia , Anticoncepcionais Orais Combinados/uso terapêuticoRESUMO
Neuroendocrine differentiation (NED) represents a possible androgen receptor pathway inhibitors (ARPI) resistance mechanism in metastatic castration resistance prostate cancer (mCRPC). As mCRPC with NED has been excluded from clinical trials evaluating ARPI efficacy, this study investigates the prognostic impact of NED in mCRPC patients treated with ARPIs. Methods: We retrospectively analyzed 327 mCRPC patient data treated with Enzalutamide or Abiraterone in the first and second or successive lines of treatment. NED was assessed using prostate biopsy samples through immunohistochemical staining. Results: NED was confirmed in 32/327 (9.8%) mCRPC patients. In the overall population, mCRPC with NED showed worse PFS (4.38 vs. 11.48 months HR 2.505 [1.71-3.68] p < 0.05), disease control rate (DCR), and PSA response. In the first line setting, mCRPC with NED demonstrated worse PFS (8.5 vs. 14.9 months HR 2.13 [1.18-3.88], p < 0.05). Similarly, in the second or successive lines, mCRPC with NED showed worse PFS (4.0 vs. 7.5 months HR 2.43 [1.45-4.05] p < 0.05), DCR, PSA response and OS (12.53 vs. 18.03 months HR 1.86 [1.12-3.10] p < 0.05). The adverse impact of NED on PFS was consistence across all subgroups; we also noted a trend of worse PFS in patients with high vs. low NED. Conclusions: In our study, mCRPC with NED treated with Enzalutamide or Abiraterone showed worse clinical outcomes. NED assessment should be considered to optimize treatment decisions in the mCRPC setting.
Assuntos
Androstenos , Benzamidas , Nitrilas , Feniltioidantoína , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Feniltioidantoína/uso terapêutico , Feniltioidantoína/farmacologia , Nitrilas/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Estudos Retrospectivos , Androstenos/uso terapêutico , Androstenos/farmacologia , Idoso , Pessoa de Meia-Idade , Diferenciação Celular/efeitos dos fármacos , Metástase Neoplásica , Idoso de 80 Anos ou mais , Resultado do Tratamento , Células Neuroendócrinas/patologia , Células Neuroendócrinas/metabolismo , Células Neuroendócrinas/efeitos dos fármacosRESUMO
INTRODUCTION: Glioblastoma (GBM) poses a significant challenge in oncology, with median survival times barely extending beyond a year due to resistance to standard therapies like temozolomide (TMZ). This study introduces a novel therapeutic strategy combining progesterone (Prog) and abiraterone (Abi) aimed at enhancing GBM treatment efficacy by modulating the tumor microenvironment and augmenting NK cell-mediated immunity. METHODS: We employed in vitro and in vivo GBM models to assess the effects of Prog and Abi on cell viability, proliferation, apoptosis, and the immune microenvironment. Techniques included cell viability assays, Glo-caspase 3/7 apoptosis assays, RNA-seq and qPCR for gene expression, Seahorse analysis for mitochondrial function, HPLC-MS for metabolomics analysis, and immune analysis by flow cytometry to quantify NK cell infiltration. RESULTS: Prog significantly reduced the IC50 of Abi in TMZ-resistant GBM cell, suggesting the enhanced cytotoxicity. Treatment induced greater apoptosis than either agent alone, suppressed tumor growth, and prolonged survival in mouse models. Notably, there was an increase in CD3-/CD19-/CD56+/NK1.1+ NK cell infiltration in treated tumors, indicating a shift towards an anti-tumor immune microenvironment. The combination therapy also resulted in a reduction of MGMT expression and a suppression of mitochondrial respiration and glycolysis in GBM cells. CONCLUSION: The combination of Prog and Abi represents a promising therapeutic approach for GBM, showing potential in suppressing tumor growth, extending survival, and modulating the immune microenvironment. These findings warrant further exploration into the clinical applicability of this strategy to improve outcomes for GBM patients.
Assuntos
Glioblastoma , Células Matadoras Naturais , Progesterona , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Glioblastoma/metabolismo , Glioblastoma/imunologia , Humanos , Camundongos , Animais , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/metabolismo , Progesterona/farmacologia , Androstenos/farmacologia , Androstenos/uso terapêutico , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Apoptose/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/metabolismo , Modelos Animais de DoençasRESUMO
BACKGROUND/AIM: The cytoprotective heat shock protein 27 (HSP27) acts as a protein chaperone, antioxidant, and apoptosis regulator and is involved in cytoskeletal remodeling in prostate cancer. This study was designed to assess the effect of prostate cancer therapeutics on HSP27 to identify drugs that may benefit from an HSP27 inhibitor combination therapy. MATERIALS AND METHODS: Cell counting was utilized to assess drug treatment efficiency. Changes in protein levels after drug treatment were assessed using western blot analysis. RESULTS: Abiraterone, cabazitaxel, docetaxel and enzalutamide significantly reduced cell proliferation in LNCaP and PC3 cells. Treatment with abiraterone and enzalutamide led to a significant reduction in HSP27 protein levels. In contrast, treatment with cabazitaxel and docetaxel did not change the HSP27 protein levels. CONCLUSION: Treatment with abiraterone and enzalutamide reduces HSP27 protein in an AR-independent manner and thus suppresses HSP27-correlated resistance mechanisms. However, docetaxel and cabazitaxel do not alter HSP27 protein levels, so that taxanes' efficacy may be enhanced by combining them with HSP27-inhibiting drugs.
Assuntos
Androstenos , Antineoplásicos , Benzamidas , Proliferação de Células , Docetaxel , Resistencia a Medicamentos Antineoplásicos , Proteínas de Choque Térmico HSP27 , Nitrilas , Feniltioidantoína , Neoplasias da Próstata , Taxoides , Humanos , Masculino , Taxoides/farmacologia , Taxoides/uso terapêutico , Docetaxel/farmacologia , Feniltioidantoína/farmacologia , Feniltioidantoína/análogos & derivados , Feniltioidantoína/uso terapêutico , Proteínas de Choque Térmico HSP27/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Androstenos/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chaperonas Moleculares/metabolismo , Proteínas de Choque Térmico/metabolismoRESUMO
Globally, prostate cancer is the most commonly diagnosed tumor and a cause of death in older men. Abiraterone, an orally administered irreversible CYP17 inhibitor, is employed to treat prostate cancer. However, abiraterone has several clinical limitations, such as poor water solubility, low dissolution rate, low bioavailability, and toxic side effects in the liver and kidney. Therefore, there is a need to identify high-efficiency and low-toxicity water-soluble abiraterone derivatives. In this work, we aimed to design and synthesize a series of abiraterone derivatives by methoxypoly(ethylene glycol) (mPEG) modification. Their antitumor activities and toxicology were analyzed in vitro and in vivo. The most potent compound, 2e, retained the principle of action on the CYP17 enzyme target and significantly improved the abiraterone water solubility, cell permeability, and blood safety. No significant abnormalities were observed in toxicology. mPEG-modification significantly improved abiraterone's antitumor activity and efficiency while reducing the associated toxic effects. The finding will provide a theoretical basis for future clinical application of mPEG-modified abiraterone.
Assuntos
Androstenos , Antineoplásicos , Polietilenoglicóis , Neoplasias da Próstata , Solubilidade , Masculino , Humanos , Androstenos/farmacologia , Androstenos/química , Animais , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Polietilenoglicóis/química , Camundongos , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Esteroide 17-alfa-Hidroxilase/metabolismoRESUMO
Castration-resistant prostate cancer (CRPC) is an aggressive disease with poor prognosis, and there is an urgent need for more effective therapeutic targets to address this challenge. Here, we showed that dihydroorotate dehydrogenase (DHODH), an enzyme crucial in the pyrimidine biosynthesis pathway, is a promising therapeutic target for CRPC. The transcript levels of DHODH were significantly elevated in prostate tumors and were negatively correlated with the prognosis of patients with prostate cancer. DHODH inhibition effectively suppressed CRPC progression by blocking cell cycle progression and inducing apoptosis. Notably, treatment with DHODH inhibitor BAY2402234 activated androgen biosynthesis signaling in CRPC cells. However, the combination treatment with BAY2402234 and abiraterone decreased intratumoral testosterone levels and induced apoptosis, which inhibited the growth of CWR22Rv1 xenograft tumors and patient-derived xenograft organoids. Taken together, these results establish DHODH as a key player in CRPC and as a potential therapeutic target for advanced prostate cancer.
Assuntos
Androstenos , Apoptose , Di-Hidro-Orotato Desidrogenase , Oxirredutases atuantes sobre Doadores de Grupo CH-CH , Neoplasias de Próstata Resistentes à Castração , Ensaios Antitumorais Modelo de Xenoenxerto , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/metabolismo , Animais , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Camundongos , Androstenos/farmacologia , Androstenos/uso terapêutico , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacosRESUMO
The development and discovery of steroidal drugs to cure cervical cancer is of the most important. The Claisen condensation of androstene and estrone with aromatic aldehydes was catalyzed by potassium tert. butoxide in tert. butanol to give the corresponding 2-arylidene and 16-arylidene estrone. Subsequently, the 16-arylidene estrone reacted with acid chloride in presence of quaternary amine in halogenated solvent resulting in the steroidal arylidene derivatives. Synthesis, Characterization and in vitro cytotoxic activity of arylidenes are rationalized. Fifteen compounds are synthesized and six of them were evaluated for cytotoxic activity against cervical cancer cell line. HT-3 cell line examination revealed a considerable growth inhibition. Compounds 4a, 4b, 6b, 8c, and 8d, which are estrone-based arylidenes, are the most potent of the series, with IC50 value of 7.15, 10.76, 6.37, 3.56, and 1.55 µM/ml against HT-3 cell line. In addition, molecular docking studies were performed for the steroidal arylidenes to elucidate the binding interactions. Compound 4a, 4b, 6b, 8c and 8d showed excellent binding energy. Docking studies agreed well with in vitro studies. The end result offers an alternative approach to develop steroidal arylidenes that are more effective and are based on estrone, leading to the development of novel anticancer agents.
Assuntos
Antineoplásicos , Neoplasias do Colo do Útero , Feminino , Humanos , Relação Estrutura-Atividade , Simulação de Acoplamento Molecular , Estrona/química , Linhagem Celular Tumoral , Antineoplásicos/química , Androstenos/farmacologia , Estrutura Molecular , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Relação Dose-Resposta a DrogaRESUMO
Patients with metastatic castration-resistant prostate cancer (mCRPC) are divided into three groups based on their response to Abiraterone treatment: best responder, responder, and non-responder. In the latter two groups, successful outcomes may not be achieved due to the development of drug-resistant cells in the tumor environment during treatment. To overcome this challenge, a secondary drug can be used to control the population of drug-resistant cells, potentially leading to a longer period of disease inhibition. This paper proposes using a combination of Docetaxel and Abiraterone in some polytherapy methods to control both the overall cancer cell population and the drug-resistant subpopulation. To investigate the competition and evolution of mCRPC cancer phenotypes, as in previous studies, the Evolutionary Game Theory (EGT) has been used as a mathematical modeling of evolutionary biology concepts.
Assuntos
Neoplasias de Próstata Resistentes à Castração , Humanos , Masculino , Docetaxel/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Taxoides/farmacologia , Taxoides/uso terapêutico , Androstenos/farmacologia , Androstenos/uso terapêutico , Resultado do Tratamento , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos Retrospectivos , Acetato de AbirateronaRESUMO
Abiraterone acetate has exhibited impressive results in improving progression-free survival of patients with metastatic castration-resistant prostate cancer. However, many patients may develop abiraterone resistance with a variable duration of response. Hence, identifying a remedy to overcome abiraterone resistance is critical for patients with castration-resistant prostate cancer. In this study, we aim to explore the potential of Qi Ling decoction (QLD), a traditional Chinese medicine, in attenuating abiraterone resistance in prostate cancer. Cell viability and apoptosis were respectively measured by Cell Counting Kit-8 (CCK-8) assay and flow cytometry. The protein levels were assessed by Western blotting assay. Autophagosome formation was quantified by counting LC3 puncta. We found that QLD was capable of promoting abiraterone-induced apoptosis and cell death of PC3-AbiR and DU145-AbiR cells in vitro. A combination of QLD and abiraterone yielded a better tumor inhibition effect than QLD alone and abiraterone alone. Further investigation revealed that QLD restored the abiraterone sensitivity of PC3-AbiR and DU145-AbiR cells through modulating autophagy. These findings suggest that QLD might serve as a potential remedy to enhance the therapeutical effect of abiraterone for patients with castration-resistant prostate cancer.
Assuntos
Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Qi , Androstenos/farmacologia , Androstenos/uso terapêutico , AutofagiaRESUMO
Prostate cancer is the second most common type of cancer among men. The main method of its treatment is androgen deprivation therapy, which has a wide range of side effects. One of the solutions to this challenge is the targeted delivery of drugs to prostate cancer cells. In this study, we performed the synthesis of a novel small-molecule PSMA-targeted conjugate based on abiraterone. Cytotoxicity, the induction of intracellular reactive oxygen species, and P450-cytochrome species inhibition were investigated for this conjugate PSMA-abiraterone. The conjugate demonstrated a preferential effect on prostate tumor cells, remaining inactive at up to 100 µM in human fibroblast cells. In addition, it revealed preferential efficacy, specifically on PSMA-expressing lines with a 65% tumor growth inhibition level on 22Rv1 (PSMA+) xenografts after 14-fold oral administration of PSMA-Abi at a single dose of 500 mg/kg (7.0 g/kg total dose) was observed. This compound showed significantly reduced acute toxicity with comparable efficacy compared to AbiAc.
Assuntos
Neoplasias da Próstata , Masculino , Humanos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Próstata/patologia , Antagonistas de Androgênios , Antígenos de Superfície , Androstenos/farmacologiaRESUMO
Many viruses require the maintenance of lysosomal cholesterol homeostasis for a successful infection; however, the role of lysosomal cholesterol homeostasis in the alphaherpesvirus life cycle is not clear. Here we show that the lysosomal cholesterol transport inhibitor U18666A interferes with the replication of pseudorabies virus (PRV), a member of the alphaherpesvirus subfamily. The treatment with U18666A caused a significant reduction in the production of infectious virus particles. The U18666A treatment was shown to suppress the release of PRV particles. Pretreating PRV virions with U18666A did not affect virus production, whereas pretreating target cells with U18666A led to a substantial reduction in virus yield. Our previous study showed that two cyclodextrin derivatives, 2-hydroxypropyl-ß-cyclodextrin (HPßCD) and 2-hydroxypropyl-γ-cyclodextrin (HPγCD), can rescue the cholesterol accumulation defect in primary fibroblasts derived from a Niemann-Pick disease type C (NPC) patient. Here, we demonstrate that treatment with HPßCD or HPγCD not only rescues the U18666A-induced cholesterol accumulation but also rescues the U18666A-induced inhibition of PRV production. Collectively, our data suggest that U18666A interferes with PRV infection via altering cellular functions that are critical for the viral life cycle and may include lysosomal cholesterol homeostasis.
Assuntos
Anticolesterolemiantes , Herpesvirus Suídeo 1 , 2-Hidroxipropil-beta-Ciclodextrina/farmacologia , Androstenos/farmacologia , Animais , Anticolesterolemiantes/farmacologia , Colesterol , HumanosRESUMO
Cancer remains one of the leading causes of death, worldwide. In addition, the lack of efficacy and selectivity of chemotherapeutic agents for cancer cells is a challenge that needs to be addressed through the development of new drugs. Since aminosteroids are of interest in fighting cancer, our group previously reported antiproliferative activity on several cancer cell lines of two representatives, RM-133 and RM-581. To extend the structure-activity relationship study of aminosteroids, of which RM-133 (androstane) and RM-581 (estrane) are the main candidates, we performed the chemical synthesis and biological evaluation on lung (SHP-77), breast (T-47D) and prostate (DU-145, PC-3 and LAPC-4) cancer cells of four analogues of RM-581. We moved the functionalized side chain from position 2 of the androstane and estrane derivatives to incorporate it into a new chain located at position 17. Chemical synthesis took place in 2 steps from steroidal side-chain carboxylic acids, allowing to obtain 4 steroid derivatives with acceptable yields, which were fully characterized by nuclear magnetic resonance spectroscopy (1H and 13C NMR). After the evaluation of compounds 12-15, lower antiproliferative activities varying from 12 to 54%, 0-33% and 0-63% were observed for SHP-77, DU-145 and PC-3 cell lines, respectively, while higher activities varying from 33 to 62% and 45-84% were observed for T-47D and LAPC-4 cell lines, respectively, when tested at 10 µM. Overall, it was observed that these aminosteroids have a lower cytotoxic activity than that of RM-581 and, that moving the side chain from steroid position C2 to C17 is clearly detrimental for antiproliferative activity. However, this work has enabled us to expand our knowledge of the structural requirements to maintain the anticancer activity of aminosteroid derivatives.
Assuntos
Androstenos , Antineoplásicos , Androstanos/farmacologia , Androstenos/química , Androstenos/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células , Estranos/química , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Esteroides/farmacologia , Relação Estrutura-AtividadeRESUMO
INTRODUCTION: Castration-resistant prostate cancer (CRPC) remains dependent on androgen receptor (AR) signalling, which is largely driven by conversion of adrenal androgen precursors lasting after castration. Abiraterone, an inhibitor of the steroidogenic enzyme CYP17A1, has been demonstrated to reduce adrenal androgen synthesis and prolong CRPC patient survival. To study mechanisms of resistance to castration and abiraterone, we created coculture models using human prostate and adrenal tumours. MATERIALS AND METHODS: Castration-naïve and CRPC clones of VCaP were incubated with steroid substrates or cocultured with human adrenal cells (H295R) and treated with abiraterone or the antiandrogen enzalutamide. Male mice bearing VCaP xenografts with and without concurrent H295R xenografts were castrated and treated with placebo or abiraterone. Response was assessed by tumour growth and PSA release. Plasma and tumour steroid levels were assessed by LC/MS-MS. Quantitative polymerase chain reaction determined steroidogenic enzyme, nuclear receptor and AR target gene expression. RESULTS: In vitro, adrenal androgens induced castration-naïve and CRPC cell growth, while precursors steroids for de novo synthesis did not. In a coculture system, abiraterone blocked H295R-induced growth of VCaP cells. In vivo, H295R promoted castration-resistant VCaP growth. Abiraterone only inhibited VCaP growth or PSA production in the presence of H295R. Plasma steroid levels demonstrated CYP17A1 inhibition by abiraterone, whilst CRPC tumour tissue steroid levels showed no evidence of de novo intratumoural androgen production. Castration-resistant and abiraterone-resistant VCaP tumours had increased levels of AR, AR variants and glucocorticoid receptor (GR) resulting in equal AR target gene expression levels compared to noncastrate tumours. CONCLUSIONS: In our model, ligand-dependent AR-regulated regrowth of CRPC was predominantly supported via adrenal androgen precursor production while there was no evidence for intratumoural androgen synthesis. Abiraterone-resistant tumours relied on AR overexpression, expression of ligand-independent AR variants and GR signalling.
Assuntos
Androgênios , Neoplasias de Próstata Resistentes à Castração , Androgênios/metabolismo , Androstenos/farmacologia , Androstenos/uso terapêutico , Animais , Linhagem Celular Tumoral , Humanos , Ligantes , Masculino , Camundongos , Nitrilas/uso terapêutico , Orquiectomia , Antígeno Prostático Específico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Receptores de GlucocorticoidesRESUMO
Viruses utilize cellular lipids and manipulate host lipid metabolism to ensure their replication and spread. Therefore, the identification of lipids and metabolic pathways that are suitable targets for antiviral development is crucial. Using a library of compounds targeting host lipid metabolic factors and testing them for their ability to block pseudorabies virus (PRV) and vesicular stomatitis virus (VSV) infection, we found that U18666A, a specific inhibitor of Niemann-Pick C1 (NPC1), is highly potent in suppressing the entry of diverse viruses including pseudotyped severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). NPC1 deficiency markedly attenuates viral growth by decreasing cholesterol abundance in the plasma membrane, thereby inhibiting the dynamics of clathrin-coated pits (CCPs), which are indispensable for clathrin-mediated endocytosis. Significantly, exogenous cholesterol can complement the dynamics of CCPs, leading to efficient viral entry and infectivity. Administration of U18666A improves the survival and pathology of PRV- and influenza A virus-infected mice. Thus, our studies demonstrate a unique mechanism by which NPC1 inhibition achieves broad antiviral activity, indicating a potential new therapeutic strategy against SARS-CoV-2, as well as other emerging viruses.
Assuntos
Androstenos/farmacologia , Clatrina/fisiologia , Invaginações Revestidas da Membrana Celular/fisiologia , Vírus de DNA/efeitos dos fármacos , Proteína C1 de Niemann-Pick/fisiologia , Vírus de RNA/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos , Vírus de DNA/fisiologia , Proteína C1 de Niemann-Pick/antagonistas & inibidores , Vírus de RNA/fisiologiaRESUMO
Some relationship between abnormal cholesterol content and impairment of insulin/insulin-like growth factor I (IGF-1) signaling has been reported in the pathogenesis of Alzheimer's disease (AD). However, the underlying mechanism of this correlation remains unclear. It is known that 3-ß hydroxycholesterol Δ 24 reductase (DHCR24) catalyzes the last step of cholesterol biosynthesis. To explore the function of cholesterol in the pathogenesis of AD, we depleted cellular cholesterol by targeting DHCR24 with siRNA (siDHCR24) or U18666A, an inhibitor of DHCR24, and studied the effect of the loss of cholesterol on the IGF-1-Akt signaling pathway in vitro and in vivo. Treatment with U18666A reduced the cellular cholesterol level and blocked the anti-apoptotic function of IGF-1 by impairing the formation of caveolae and the localization of IGF-1 receptor in caveolae of the PC12 cells. Downregulation of the DHCR24 expression induced by siRNA against DHCR24 also yielded similar results. Furthermore, the phosphorylation levels of IGF-1 receptor, insulin receptor substrate (IRS), Akt, and Bad in response to IGF-1 were all found to decrease in the U18666A-treated cells. Rats treated with U18666A via intracerebral injection also exhibited a significant decrease in the cholesterol level and impaired activities of IGF-1-related signaling proteins in the hippocampus region. A significant accumulation of amyloid ß and a decrease in the expression of neuron-specific enolase (NSE) was also observed in rats with U18666A. Finally, the Morris water maze experiment revealed that U18666A-treated rats showed a significant cognitive impairment. Our findings provide new evidence strongly supporting that a reduction in cholesterol level can result in neural apoptosis via the impairment of the IGF-1-Akt survival signaling in the brain.
Assuntos
Encéfalo/fisiologia , Colesterol/biossíntese , Fator de Crescimento Insulin-Like I/metabolismo , Neurônios/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/fisiologia , Androstenos/farmacologia , Animais , Aprendizagem em Labirinto , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/genética , Neurônios/efeitos dos fármacos , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética , Células PC12 , RatosRESUMO
Amyloid ß (Aß) peptides generated from the amyloid precursor protein (APP) play a critical role in the development of Alzheimer's disease (AD) pathology. Aß-containing neuronal exosomes, which represent a novel form of intercellular communication, have been shown to influence the function/vulnerability of neurons in AD. Unlike neurons, the significance of exosomes derived from astrocytes remains unclear. In this study, we evaluated the significance of exosomes derived from U18666A-induced cholesterol-accumulated astrocytes in the development of AD pathology. Our results show that cholesterol accumulation decreases exosome secretion, whereas lowering cholesterol increases exosome secretion, from cultured astrocytes. Interestingly, exosomes secreted from U18666A-treated astrocytes contain higher levels of APP, APP-C-terminal fragments, soluble APP, APP secretases and Aß1-40 than exosomes secreted from control astrocytes. Furthermore, we show that exosomes derived from U18666A-treated astrocytes can lead to neurodegeneration, which is attenuated by decreasing Aß production or by neutralizing exosomal Aß peptide with an anti-Aß antibody. These results, taken together, suggest that exosomes derived from cholesterol-accumulated astrocytes can play an important role in trafficking APP/Aß peptides and influencing neuronal viability in the affected regions of the AD brain.
Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Astrócitos/metabolismo , Colesterol/metabolismo , Exossomos/metabolismo , Peptídeos beta-Amiloides/metabolismo , Androstenos/farmacologia , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/ultraestrutura , Autofagia/efeitos dos fármacos , Catepsina D/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Exossomos/efeitos dos fármacos , Exossomos/ultraestrutura , Feminino , Proteína 1 de Membrana Associada ao Lisossomo , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Lisossomos/ultraestrutura , Camundongos Endogâmicos BALB C , Proteínas Associadas aos Microtúbulos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , RatosRESUMO
BACKGROUND: Low body mass index (BMI) and low serum albumin levels are suggested indicators of malnutrition and are associated with poor outcomes in cancer patients. Decreasing androgen can alter lipid metabolism, so the prognostic value of BMI may change in metastatic castration-resistant prostate cancer (mCRPC) patients receiving abiraterone. We aimed to delineate the prognostic value of BMI, serum albumin, and BMI and serum albumin (ALB) combined. MATERIALS AND METHODS: A post hoc analysis was performed on data from two randomized clinical trials evaluating the efficacy of abiraterone in chemotherapy-pretreated and -naïve mCRPC patients. Survival analysis was conducted using Kaplan-Meier and Cox proportional hazard methods. RESULTS: A total of 2,205 mCRPC patients were included in this study. Low ALB independently predicted the OS in both cohorts (HR, 1.54; 95%CI, 1.34-1.78 and HR, 1.40; 95%CI, 1.21-1.64, respectively), while low BMI independently predicted the OS only in the post-chemotherapy cohort (HR, 1.30; 95%CI, 1.12-1.50) but not in the pre-chemotherapy cohort (HR, 1.19; 95%CI, 0.98-1.43). By combining BMI (<25 kg/m2 or ≥30 kg/m2 ) and ALB (<4 g/dl or >4 g/dl), the four groups were characterized and their HRs were 1, 0.60 (95%CI, 0.47-0.76, p < 0.001), 0.75 (95%CI,0.61-0.92 p = 0.006), and 0.49 (95%CI, 0.41-0.60, p < 0.001) in post-chemotherapy patients and 1, 0.64 (95%CI, 0.46-0.89, p = 0.008), 0.75 (95%CI,0.58-0.98 p = 0.034), and 0.55 (95%CI, 0.42-0.72, p < 0.001) in chemotherapy-naïve patients, respectively. CONCLUSIONS: Our results demonstrate that the combination of BMI and ALB better characterizes the risk groups irrespective of previous chemotherapy. Patients with high BMI but low ALB have higher risk of death than patients with low BMI but high ALB.
Assuntos
Albuminas/metabolismo , Androstenos/uso terapêutico , Índice de Massa Corporal , Neoplasias de Próstata Resistentes à Castração/mortalidade , Androstenos/farmacologia , Método Duplo-Cego , Humanos , Masculino , Prognóstico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Análise de Sobrevida , Resultado do TratamentoRESUMO
Abiraterone, a novel androgen synthesis inhibitor, has been approved for castration-resistant prostate cancer (CRPC) treatment. However, most patients eventually acquire resistance to this agent, and the underlying mechanisms related to this resistance remain largely unelucidated. Lysine acetyltransferase 2 A (KAT2A) has been reported to enhance transcriptional activity for certain histone or non-histone proteins through the acetylation and post-translational modification of the androgen receptor (AR). Therefore, we hypothesised that KAT2A might play a critical role in the resistance of prostate tumours to hormonal treatment. In this study, we found that KAT2A expression was increased in abiraterone-resistant prostate cancer C4-2 cells (C4-2-AbiR). Consistently, elevated expression of KAT2A was observed in patients with prostate cancer exhibiting high-grade disease or biochemical recurrence following radical prostatectomy, as well as in those with poor clinical survival outcomes. Moreover, KAT2A knockdown partially re-sensitised C4-2-AbiR cells to abiraterone, whereas KAT2A overexpression promoted abiraterone resistance in parental C4-2 cells. Consistent with this finding, KAT2A knockdown rescued abiraterone sensitivity and inhibited the proliferation of C4-2-AbiR cells in a mouse model. Mechanistically, KAT2A directly acetylated the hinge region of the AR, and induced AR translocation from the cytoplasm to the nucleus, resulting in increased transcriptional activity of the AR-targeted gene prostate specific antigen (PSA) leading to resistance to the inhibitory effect of abiraterone on proliferation. Taken together, our findings demonstrate a substantial role for KAT2A in the regulation of post-translational modifications in AR affecting CRPC development, suggesting that targeting KAT2A might be a potential strategy for CRPC treatment.
Assuntos
Androstenos/farmacologia , Núcleo Celular/metabolismo , Resistencia a Medicamentos Antineoplásicos , Histona Acetiltransferases/metabolismo , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores Androgênicos/metabolismo , Acetilação , Animais , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Histona Acetiltransferases/genética , Humanos , Lisina/metabolismo , Masculino , Camundongos Nus , Prognóstico , Antígeno Prostático Específico/metabolismo , Transporte Proteico/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
BACKGROUND: To use ddPCR to quantify plasma exosomal class III ß-tubulin (ßIII-tubulin, TUBB3, encoded by the TUBB3 gene) mRNA expression in metastatic castration-resistant prostate cancer (mCRPC) patients, and study the association of this expression with abiraterone efficacy. METHODS: Blood samples were prospectively collected from 52 mCRPC patients using abiraterone as first-line therapy to measure plasma exosomal TUBB3 mRNA expression value before the initiation of abiraterone. Study endpoints were PSA response rate, PSA-progression-free survival (PSA-PFS), and overall survival (OS, from CRPC to death). RESULTS: Patients with positive exosomal TUBB3 expression showed shorter PSA-PFS (negative TUBB3 vs. positive TUBB3: 11.0 vs. 7.9 months; p = 0.014). Further analysis demonstrated that patients with strongly positive exosomal TUBB3 (>20 copies/20 µl) was associated with even shorter PSA-PFS (negative TUBB3 vs. positive TUBB3 [<20 copies/20 µl] vs. strongly positive TUBB3 [>20 copies/20 µl]: 11.0 vs. 8.3 vs. 3.6 months, p = 0.005). In multivariate analyzes, TUBB3 (+) (HR: 2.114, p = 0.033) and ECOG score >2 (HR: 3.039, p = 0.006) were independent prognosticators of poor PSA-PFS. PSA response and OS did not present significant differences. CONCLUSION: The exosomal TUBB3 mRNA expression level is associated with poor PSA-PFS of abiraterone in mCRPC patients. The detection of exosomal TUBB3 can be valuable in their management.