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Gain of function mutations in the pore forming Kir6 subunits of the ATP sensitive K+ channels (K(ATP) channels) of pancreatic ß-cells are the major cause of neonatal diabetes in humans. In this study, we show that in insulin secreting mouse ß-cell lines, gain of function mutations in Kir6.1 result in a significant connexin36 (Cx36) overexpression, which form gap junctional connections and mediate electrical coupling between ß-cells within pancreatic islets. Using computational modeling, we show that upregulation in Cx36 might play a functional role in the impairment of glucose stimulated Ca2+ oscillations in a cluster of ß-cells with Kir6.1 gain of function mutations in their K(ATP) channels (GoF-K(ATP) channels). Our results show that without an increase in Cx36 expression, a gain of function mutation in Kir6.1 might not be sufficient to diminish glucose stimulated Ca2+ oscillations in a ß-cell cluster. We also show that a reduced Cx36 expression, which leads to loss of coordination in a wild-type ß-cell cluster, restores coordinated Ca2+ oscillations in a ß-cell cluster with GoF-K(ATP) channels. Our results indicate that in a heterogenous ß-cell cluster with GoF-K(ATP) channels, there is an inverted u-shaped nonmonotonic relation between the cluster activity and Cx36 expression. These results show that in a neonatal diabetic ß-cell model, gain of function mutations in the Kir6.1 cause Cx36 overexpression, which aggravates the impairment of glucose stimulated Ca2+ oscillations.
Assuntos
Células Secretoras de Insulina , Canais KATP , Regulação para Cima , Células Secretoras de Insulina/metabolismo , Animais , Camundongos , Canais KATP/genética , Canais KATP/metabolismo , Conexinas/genética , Conexinas/metabolismo , Mutação com Ganho de Função , Proteína delta-2 de Junções Comunicantes , Sinalização do Cálcio , Modelos Biológicos , Cálcio/metabolismo , HumanosRESUMO
BACKGROUND: This study aimed to identify a candidate gene associated with paclitaxel (PTX) resistance and to evaluate functionally its biological role in the PTX-resistant head and neck squamous cell carcinoma (HNSCC) cell lines and clinical specimens. METHODS: Microarray data series containing samples of different types of cancers resistant to PTX were analyzed and then a candidate gene associated with PTX resistance was identified using various bioinformatics tools. After the suppression of the target gene expression, changes in cell viability and colony-forming ability were evaluated in PTX-resistant FaDu and SCC-9 cell lines. RESULTS: Bioinformatics analyses of upregulated genes in PTX-resistant cancer cells indicated that OAS3 was associated with PTX resistance. The downregulation of OAS3 expression significantly reduced the viability and colony-forming capacity of PTX-resistant SCC-9 cells by inducing apoptosis and cell cycle arrest at G0/G1 phase. CONCLUSIONS: The therapeutic targeting of OAS3 may resensitize PTX-resistant HNSCC cells with high OAS3 expression to PTX treatment.
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Carcinoma de Células Escamosas , Biologia Computacional , Resistencia a Medicamentos Antineoplásicos , Neoplasias de Cabeça e Pescoço , Paclitaxel , Humanos , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/patologia , Linhagem Celular Tumoral , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Apoptose/efeitos dos fármacos , Apoptose/genética , 2',5'-Oligoadenilato Sintetase/genética , Masculino , Feminino , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Pessoa de Meia-IdadeRESUMO
Head and neck cancer (HNC) is the sixth most common malignancy worldwide. Although current modalities offer a wide variety of therapy choices, head and neck carcinoma has poor prognosis due to its diagnosis at later stages and development of resistance to current therapeutic tools. In the current study, we aimed at exploring the roles of miR-200c-3p during head and neck carcinogenesis and acquisition of taxol resistance. We analyzed miR-200c-3p levels in HNC clinical samples and cell lines using quantitative real-time polymerase chain reaction and evaluated the effects of differential miR-200c-3p expression on cancer-related cellular phenotypes using in-vitro tools. We identified and characterized a direct target of miR-200c-3p using in-silico tools, luciferase and various in-vitro assays. We investigated potential involvement of miR-200c-3p/SSFA2 axis in taxol resistance in-vitro. We found miR-200c-3p expression as significantly downregulated in both HNC tissues and cells compared to corresponding controls. Ectopic miR-200c-3p expression in HNC cells significantly inhibited cancer-related phenotypes such as viability, clonogenicity, migration, and invasion. We, then, identified SSFA2 as a direct target of miR-200c-3p and demonstrated that overexpression of SSFA2 induced malignant phenotypes in HNC cells. Furthermore, we found reduced miR-200c-3p expression in parallel with overexpression of SSFA2 in taxol resistant HNC cells compared to parental sensitive cells. Both involved in intracellular cytoskeleton remodeling, we found that SSFA2 works collaboratively with IP3R1 to modulate resistance to taxol in HNC cells. When considered collectively, our results showed that miR-200c-3p acts as a tumor suppressor microRNA and targets SSFA2/IP3R1 axis to sensitize HNC cells to taxol.
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Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço , Receptores de Inositol 1,4,5-Trifosfato , MicroRNAs , Paclitaxel , Humanos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/genética , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Paclitaxel/farmacologiaRESUMO
In this study, we researched the reactions of 5-(5-bromofuran-2-yl)-4-methyl-1,2,4-triazole-3-thiol and 5-thiophene-(3-ylmethyl)-4R-1,2,4-triazole-3-thiols with some halogen-containing compounds, a number of new compounds were synthesized (1.1-1.5 and 2.1-2.8). These compounds showed excellent to good inhibitory activities on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. For obtaining the effects of these compounds on AChE and BChE enzymes were determined spectrophotometrically according to Ellman. IC50 values of these enzymes were ranging between 1.63 and 17.68 nM for AChE and 8.71 and 84.02 nM for BChE. After, prostate cancer is the second leading cause of cancer-related mortality for men over the age of 65 in developed countries. Current treatment options remain limited in the treatment of advanced-stage prostate cancer leading to biochemical recurrence in almost 40% of the patients. Therefore, there is an urgent need for development of novel therapeutic tools for treatment of prostate cancer patients. In this study, we aimed at analyzing the potential of all compounds against prostate cancer cells. We found that, of the tested compounds, 2.1, 2.2 and 2.3 showed significant cytotoxic activities against PC3 prostate cancer cells, although their effect on the viability of normal prostate cells was limited. These findings suggest their selective targeting potential for prostate cancer cells and offer them as candidate therapeutic agents against prostate cancer. The inhibitory activities of some chemical compounds, such as (1.1-1.5 and 2.1-2.8) were assessed by performing the molecular docking study in the presence of AChE, BChE and prostate cancer protein. MM/GBSA methods are calculated binding free energy. Finally, ADME/T analysis was performed to examine the drug properties of the 13 studied molecules.Communicated by Ramaswamy H. Sarma.
Assuntos
Butirilcolinesterase , Neoplasias da Próstata , Triazóis , Humanos , Masculino , Butirilcolinesterase/metabolismo , Acetilcolinesterase/química , Inibidores da Colinesterase/química , Simulação de Acoplamento Molecular , Desenho de Fármacos , Neoplasias da Próstata/tratamento farmacológico , Relação Estrutura-Atividade , Estrutura MolecularRESUMO
Peri-implantitis develops in 43.3% of implant patients, which affects tissues around the implant that may ultimately cause implant loss if not treated properly. Due to difficulties in detecting peri-implantitis in its early phases, implant failures are constantly on the rise. Therefore, new specific molecular markers need to be identified to prevent or limit disease progression in peri-implantitis patients. We investigated levels of CXCL9, CXCL12, and CXCL14 in saliva samples of 45 patients with commercially pure grade 4/5 Titanium-Aluminum-Vanadium implants. We analyzed the correlation of the chemokine levels using Pearson's Correlation test and investigated their power to discriminate peri-implantitis vs. non-peri-implantitis patients using receiver operating characteristic analysis. Our in silico investigation revealed CXCL9, CXCL12, and CXCL14 as predicted targets of miR-4484, which has been demonstrated as a powerful biomarker candidate for early detection of peri-implantitis in our previous study. We measured high CXCL9 and low CXCL14 levels in the saliva of peri-implantitis patients. We also reported that the CXCL14 level showed a significant positive correlation with miR-4484. Besides, CXCL14 together with miR-4484 in saliva differentiated peri-implantitis patients from non-peri-implantitis individuals with 100% success. We offer differential expressions of CXCL14 and miR-4484 in the saliva of patients with peri-implantitis as potential salivary biomarkers for early detection of this disease.
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A series of biologically active novel Mannich bases containing with a 1H-1,2,4-triazole-5-one ring were developed to evaluate the cytotoxic activity. For this purpose, the synthesized Schiff Bases (S1-5) were reacted with formaldehyde and morpholine, which is a secondary amine to yield novel N-Mannich bases (M1-5) via the Mannich reaction. The structures of the compounds (M1-5) were determined structurally employing 1H/13C-NMR, IR and elemental analysis. In this study, we evaluated the cytotoxic potential of the compounds (M1-5) on the human hypopharyngeal carcinoma FaDu cells. We found that the compound (M3) possesses a significant anticancer feature against FaDu cells that might be evaluated with further in vitro and in vivo studies to understand its anticancer potential better. Lastly, comparisons were made using molecular docking calculations to find the theoretical activities of the compounds (M1-5). The docking score parameter of the compound (M3) against the 2DO4 protein is -5.67, the docking score parameter against the 5JPZ protein is -5.72, and finally, the docking score parameter against the 2H80 protein is -5.50. Molecular dynamic calculations are made for 0-100 ns. The ADME/T calculations were performed to find the drug potential of the compounds (M1-5). The results suggest that our drug candidate compound exhibits strong potential for co-administration with the antigen structures, owing to the low rate of interactions that decreased over time.Communicated by Ramaswamy H. Sarma.
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Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignant cancer type worldwide. Although the therapeutic modalities currently used for patients with HNSCC improved in recent decades, HNSCC prognosis is still poor. Therefore, it is an urgent necessity to understand the pathogenesis of HNSCC, to develop novel and effective treatment strategies, and to characterize and identify the oncogenes that are responsible for an aggressive HNSCC phenotype. In this study, we aimed to better understand the roles of miR-1825 in the pathogenesis of HNSCC. We examined the impacts of miR-1825 deregulation on the cancer-associated phenotypes using in vitro tests evaluating cell viability, clonogenicity, cell migration, invasion, apoptosis, and stem cell characteristics. In addition, we investigated the effects of miR-1825 overexpression on the tumor formation capacity of head and neck cancer cells in vivo using nude mice. We searched for potential targets of miR-1825 using microarray analysis and luciferase assay. We found that miR-1825 expression is upregulated in head and neck cells and clinical tumor samples in comparison to corresponding controls, where it potentially acts as an oncogene. We, then, showed that ectopic miR-1825 overexpression promotes cellular phenotypes related to head and neck cancer progression in vitro and has a stimulating potential on cancer formation in vivo. We also identified FREM1 as a direct target of miR-1825 and demonstrated its reduced expression in HNSCC samples using immunohistochemistry analysis. Collectively, we suggest that the miR-1825/FREM1 axis serves as an important mediator of HNSCC development, where miR-1825 acts as an oncogene.
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Head and neck squamous cell carcinoma (HNSCC) is one of the most aggressive neoplasms, which requires more effective prevention and treatment modalities. Previous studies found that protein O-fucosyltransferase 1 (POFUT1) upregulation promotes carcinogenesis, although the potential roles, underlying molecular mechanisms, and biological implications of POFUT1 in HNSCC were not investigated. In this study, in silico analyses referred POFUT1 as a potential oncogene in HNSCC. Further analysis of tumor and normal tissue samples as well as HNSCC cells with quantitative real-time polymerase chain reaction, Western blot analysis, and immunohistochemistry showed significant overexpression of POFUT1 in HNSCC clinical tumor tissue specimens and cell lines compared to corresponding controls. In vitro investigations revealed that overexpression of POFUT1 promoted phenotypes associated with cancer aggressiveness and its knockdown in HNSCC cells suppressed those phenotypes. Further xenograft experiments demonstrated that POFUT1 is an oncogene in vivo for HNSCC. Immunohistochemical analysis with human clinical samples and cancer cell-dorsal root ganglion ex-vivo coculture model showed that deregulation of POFUT1 is involved in the perineural invasion of HNSCC cells. These results suggest POFUT1 expression as a potential prognostic marker for patients with head and neck cancer and highlight its potential as a target for HNSCC therapy, although more molecular clues are needed to better define the functions of POFUT1 related to HNSCC carcinogenesis.
Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Neoplasias de Cabeça e Pescoço/genética , Fenótipo , Carcinogênese , Linhagem Celular Tumoral , Proliferação de Células/genéticaRESUMO
BACKGROUND: Oral squamous cell carcinoma (OSCC) is characterized by enhanced angiogenesis resulting in poor prognosis despite improvements in diagnostic/therapeutic techniques. Here, we aimed at investigating potential roles of miR-1825 enclosed in OSCC-derived exosomes on angiogenesis under hypoxic conditions. METHODS: Effects of miR-1825 mimic/inhibitor as well as hypoxia-induced tumor derived exosomes on human umbilical vein endothelial cells (HUVECs) were evaluated using cell viability, migration/invasion, tube formation, and spheroid-based 3D angiogenesis assays. RESULTS: Hypoxic conditions caused significant increase in miR-1825 levels in OSCC cells and hiTDEs. miR-1825 alone and within hiTDEs promoted endothelial cell viability, migration, invasion, and angiogenic potential, which is reversed via inhibition of miR-1825 expression. miR-1825 within hiTDEs altered the angiogenesis potential of HUVEC cells via deregulation of TSC2/mTOR axis. CONCLUSIONS: We showed that hypoxia led to OSCC-derived exosome mediated transfer of miR-1825 to HUVECs and enhanced angiogenesis in OSCC in vitro.
Assuntos
Carcinoma de Células Escamosas , Exossomos , Neoplasias de Cabeça e Pescoço , MicroRNAs , Neoplasias Bucais , Humanos , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Exossomos/genética , Exossomos/metabolismo , Exossomos/patologia , Neoplasias de Cabeça e Pescoço/patologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Hipóxia/metabolismo , Hipóxia/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias Bucais/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Serina-Treonina Quinases TOR/metabolismoRESUMO
Modulation of existing drugs is an attractive strategy to achieve improved activity in cancer therapy by lowering their effective dose. Preparation of relatives has been suggested and explored to improve the therapeutic effect of anticancer agents. In the current study, we attempted to modulate tamoxifen (TMX) by replacing the C-phenyl ring in its backbone with an indole or oxindole. In addition, it was possible to convert indole-modified tamoxifens to the corresponding 3,3'-bis(indolyl)methanes (BIMs) via an electrophilic substitution reaction with various benzaldehydes. We analyzed the anticancer potential of these indole-modified tamoxifens against various breast cancer cell lines and identified certain tamoxifen relatives with the potential to treat estrogen receptor (ER)-positive breast cancers, based on preliminary results of cell viability and caspase activity assays. The indole-modified tamoxifen BIM-Z,Z-35b, BIM-Z,Z-35f, and E-33 selectively reduced the viability of receptor-sensitive breast cancer cells more effectively than tamoxifen and suppressed the expression of ER-regulated genes. Moreover, Caspase-8 activity showed a specific increase in MCF-7 cells treated with these compounds. Our results indicate that these compounds may be an alternative to tamoxifen for the treatment of breast cancer.
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Head and neck cancer (HNC), which is among the deadliest malignancies, is the seventh most common cancer worldwide. How cholesterol homeostasis is linked to human cancers has long been a source of curiosity. One of the few proteins that are involved in cholesterol homeostasis is ATP-binding cassette transporter A1 (ABCA1), which is broadly expressed in numerous tissues. ABCA1 increases cholesterol efflux, inhibits cholesterol deposition in cells, and modulates anticancer activities. Therefore, it is not surprising that decreased ABCA1 activity and altered cholesterol homeostasis are implicated in the patho-physiology of HNCs. In this review, we focus on the role of cholesterol metabolism in the patho-physiology and progression of HNCs, with an emphasis on biological effects of ABCA1 transporters. We also review therapeutic approaches targeting cholesterol metabolism, as well as how combining such approaches with existing anticancer treatments may have synergistic effects and therefore open up new therapeutic avenues.
Assuntos
Transportador 1 de Cassete de Ligação de ATP , Neoplasias de Cabeça e Pescoço , Humanos , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Colesterol/metabolismoRESUMO
OBJECTIVES: Diets and nutritional habits are critical during carcinogenic processes, where a diet poor in fruits and vegetables and rich in meat and other foods of animal origin facilitates carcinogenesis. In this study, we aimed at investigating the possible involvement of vitamin D deficiency (VDD) and high cholesterol (HC) together in oral squamous cell carcinoma (OSCC) through modulating glycolysis. SUBJECTS AND METHODS: We compared total cholesterol, LDL, HDL, triglycerides, LDH, and vitamin D levels of OSCC patients and control individuals. We used GEO datasets for gene set enrichment and 4-nitroquinoline-1-oxide induced in vivo oral carcinogenesis models to investigate contribution of VDD and HC during carcinogenesis via possible modulation of glycolysis. RESULTS: We found that VDD and HC co-exist in OSCC patients, and deregulation of cholesterol and vitamin D levels results in enrichment of genes related to glycolysis. We, then, demonstrated that VDD and HC on their own and together facilitated the formation of larger tumors in 4NQO-induced in vivo cancer models, which are suppressed by glycolysis inhibition. CONCLUSION: We reported collaborative contribution of HC and VDD during oral carcinogenesis, which is mainly carried out via altering energy metabolism in tumor cells.
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Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Deficiência de Vitamina D , Ratos , Animais , Carcinoma de Células Escamosas/induzido quimicamente , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Neoplasias Bucais/genética , Carcinogênese/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço , Vitamina D , Glicólise , Deficiência de Vitamina D/complicaçõesRESUMO
This study was designed to investigate the impacts of Doxo alone and in combination with Cipro on the hepatic and cardiac CYP1A2, CYP2J3, and CYP3A1 mRNA levels. We also aimed to analyze the cardiac function by perfusing isolated rat hearts. Rats were given Doxo and/or Cipro in chronic (3-week) and acute (single-day) dosing schedules. Cardiac CYP2J3, CYP3A1, and CYP1A2 gene expression levels were measured by quantitative reverse transcription PCR. Cardiac functions of the isolated hearts were evaluated by using the Langendorff technique. Doxo alone (2.5 mg/kg) and Doxo + Cipro (2.5 mg + 20 mg/kg) significantly decreased hepatic CYP1A2 expression compared to saline, whereas Doxo (2.5 mg/kg) and Doxo + Cipro (2.5 mg + 20 mg/kg) showed significantly higher cardiac CYP1A2 expression in comparison to control. In the liver tissue, Doxo (2.5 mg/kg) and Doxo + Cipro (2.5 + 20 mg/kg) decreased the CYP2J3 expression than the control group. The Doxo (2.5 mg/kg) and Doxo + Cipro (2.5 + 20 mg/kg)-treated group had significantly higher cardiac CYP2J3 expression compared to control. Doxo (2.5 mg/kg; cumulative dose 15 mg/kg) and Doxo + Cipro (2.5 + 20 mg/kg) showed significantly higher cardiac CYP3A1 expressions than the control. Rate-pressure product (HR × LVDP)/1000) showed an overall decrease in cardiac functions of Doxo (2.5 mg/kg) and Doxo + Cipro (2.5 + 20 mg/kg)-treated group. We found considerable effects in chronic protocol; Doxo alone high dose and plus Cipro decreased hepatic CYP1A2 and CYP2J3 mRNA. On the other hand, these treatment groups exhibited an increase in the cardiac CYP1A2, CYP2J3, and CYP3A1 expression and likewise deteriorated the overall hemodynamic parameters.
Assuntos
Ciprofloxacina , Citocromo P-450 CYP1A2 , Ratos , Animais , Citocromo P-450 CYP1A2/genética , Citocromo P-450 CYP1A2/farmacologia , Ciprofloxacina/farmacologia , Doxorrubicina/toxicidade , Coração , Fígado , Cardiotoxicidade/metabolismoRESUMO
Photodynamic therapy (PDT) is an innovative, non-invasive and highly selective therapeutic modality for tumours and non-malignant diseases. BODIPY based molecules can function as new generation photosensitizers (PSs) in various PDT applications. Despite numerous conjugated PS systems are available, BODIPYs containing erlotinib lagged behind other photosensitizer units. In this study, smart photosensitizers containing BODIPY, erlotinib and hydrophilic units were prepared for the first time, their physicochemical properties and PDT effects were investigated. Compared with non-halogenated compound, halogenated derivatives possessed much lower fluorescence profile as well as the good ROS generation ability under red light. In vitro PDT studies were performed on both healthy (PNT1a) and prostate cancerous cells (PC3) to determine the selectivity of the compounds on cancerous cells and their effects under light. The halogenated conjugates, exposed to low dose of light illumination exhibited potent activity on cancer cell viability and the calculated IC50 values proved the high phototoxicity of the photosensitizers. It was also determined that the PSs have very low dark toxicity and that the light illumination and ROS formation are required for the initiation of the cell death mechanism. As a result, erlotinib modified BODIPYs could serve as promising agents in anticancer photodynamic therapy.
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Neoplasias , Fotoquimioterapia , Humanos , Fármacos Fotossensibilizantes/química , Cloridrato de Erlotinib/farmacologia , Espécies Reativas de Oxigênio , Neoplasias/tratamento farmacológicoRESUMO
PURPOSE: Development of chemoresistance is one of the major obstacles to the treatment of head and neck squamous cell carcinoma (HNSCC). The PI3K/Akt pathway, involved in drug resistance, has been found to be overactivated in > 90% of HNSCCs. Aberrant activation of the FGF receptors (FGFRs) has been reported to cause overactivation of the PI3K/Akt pathway and to be associated with the maintenance of stem cell features, which is controlled via SOX2 expression. In this study, we aimed at investigating the potential of using AZD4547, an orally bioavailable FGFR inhibitor, to overcome taxol-resistance by targeting the FGFR/Akt/SOX2 axis in HNSCC. METHODS: We initially evaluated FGFR2 and SOX2 expression using in silico tools. We analyzed the FGFR/Akt/SOX2 axis in normal/tumor tissue pairs and in recombinant FGF2 treated HNSCC cells. Next, we explored the effects of AZD4547 alone and in combination with taxol on the proliferation, migration and colony forming capacities of parental/taxol-resistant cells using in vitro models. RESULTS: We found that the p-FGFR, p-AKT, p-GSK-3ß and SOX2 expression levels were higher in tumor tissues than in its corresponding normal tissues, and that AZD4547 effectively suppressed the expression of FGFR and its downstream targets in recombinant FGF2 treated HNSCC cells. We also found that AZD4547 diminished the viability, migration and colony forming capacity of HNSCC cells, and that co-treatment with taxol potentiated the impact of taxol on these cells. Finally, we found that AZD4547 inhibited the overexpressed FGFR/Akt/SOX2 axis and profoundly suppressed cancer-related phenotypes in taxol-resistant HNSCC cells. CONCLUSION: From our data we conclude that AZD4547 may increase the impact of taxol during HNSCC treatment. We suggest AZD4547 as a therapeutic agent to overcome taxol-resistance.
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Resistencia a Medicamentos Antineoplásicos , Neoplasias de Cabeça e Pescoço , Proteínas Proto-Oncogênicas c-akt , Benzamidas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Glicogênio Sintase Quinase 3 beta/metabolismo , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Paclitaxel/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Piperazinas/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirazóis/farmacologia , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Fatores de Transcrição SOXB1/metabolismoRESUMO
Idiopathic male infertility (IMI) is the absence of a reason to explain a patient's infertility, and it occurs at a frequency of %31. In this study we aimed to investigate the oxidant/antioxidant status of patients with IMI and compare their results to those of healthy controls.A total of 79 patients with IMI (group 1) and 90 healthy individuals (group 2) were included in the study. We used Erel & Neselioglu's thiol/disulfide homeostasis test. Collective and individual measurements of oxidative/antioxidative balance components were carried out by this novel thiol/disulfide homeostasis test. Serum antioxidant (total thiol (toSH), native thiol (SH)) and oxidant (disulfide (SS)) levels of all study participants were measured. The results from both groups were compared and analyzed statistically. After toSH, SH, and SS levels were determined, SS/toSH% and SS/SH% levels for each group were analyzed separately and compared statistically.The toSH, SH levels, and SS/SH%, SS/toSH% ratios were significantly different between the groups (p < 0.05).While antioxidant parameters (toSH and SH values) decreased in group1, oxidant parameters (SS/SH%, SS/toSH%) increased significantly. Although SS values were higher in group 1, the difference was not significant (p = 0.214). The SH cutoff value of 507.15 µmol/L predicted the probability of IMI development with 72.2% sensitivity and 74.4% specificity and toSH cutoff value of 545.45 µmol/L predicted IMI development with 70.9% sensitivity and 73.3 specificity (p < 0.001). Multivariate logistic regression analysis showed that the only independent risk factor for the development of IMI is SH. Patients with IMI had a significant change in their thiol/disulfide homeostasis, which suggests the involvement of this imbalance in the pathophysiology of IMI. Furthermore, these results also support the notion of the involvement of oxidative stress in sperm dysfunction. It also points to the possibility of using antioxidants in IMI treatment.Abbreviations: IMI: idiopathic male infertility; toSH: total thiol; SH: native thiol; SS: disulfide; OS: oxidative stress; ROS: reactive oxygen species; DCF: dichlorofluorescein; MiOXSYS: male infertility oxidative system; MOSI: male oxidative stress infertility; LC: L-carnitine; LAC: L-acetylcarnitine; Vit: vitamin; OAT: oligoasthenozoospermia; TMSC: total motile sperm count; WHO: World Health Organization; BMI: body mass index; DTNB: 5,5'-dithiobis-2-nitrobenzoic acid; CV: coefficient variation; ROC: receiver operating characteristic; PR: progressive, NP: non-progressive.
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Dissulfetos , Infertilidade Masculina , Antioxidantes , Biomarcadores , Homeostase/fisiologia , Humanos , Infertilidade Masculina/etiologia , Masculino , Oxidantes , Estresse Oxidativo , Compostos de SulfidrilaRESUMO
OBJECTIVE: The aim of this study was to analyze the results of microsurgical testicular sperm extraction (micro-TESE) and investigate the potential factors that may affect the successful sperm retrieval and timing of micro-TESE. METHODS: A total of 56 patients with nonobstructive azoospermia (NOA) who underwent micro-TESE procedure between January 2017 and December 2019 were retrospectively analyzed. The patient age, marriage duration, infertility duration, smoking, chronic illness, varicocele status, previous scrotal surgeries, and the presence of genetic disease were noted by an urologist for all patients. RESULTS: The mean age of patients was 33.28±4.4 (22-44) years. Our total sperm-retrieval rate was 55.4% (n:31). Sixteen (28.6%) pregnancies were achieved and 15 (26.8%) healthy live births could be managed. Only the marriage duration (p=0.016) and infertility duration (p=0.015) were detected to be the significant factors to manage successful sperm retrieval. Men with NOA younger than 35.2 years and having a female partner younger than 36.9 years seemed to have the best chance to have a living healthy baby. CONCLUSIONS: The fertility decreased by both male and female age and for men with NOA. The early visit to doctor seemed to have positive effect.
Assuntos
Azoospermia , Adulto , Criança , Feminino , Humanos , Masculino , Gravidez , Estudos Retrospectivos , Recuperação Espermática , Espermatozoides , TestículoRESUMO
Daucus carota L. ssp. major (DCM) plant is widely used in traditional medicine to treat some types of cancer and various diseases. Therefore, we evaluated the biological activities of this plant to define its effects against prostate cancer (PCa), Alzheimer's disease (AD), oxidation, and diabetes mellitus (DM) as well as identified its phenolic composition. To determine the anti-cancer properties of the plant extract, we treated PCa cells with the extract at a concentration range of 0.25, 0.5, 1, 2, and 4 mg/ml. Significant results were obtained against the PC3 cells compared to normal PNT1a prostate epithelial cells. As a result of precise measurements at the millimolar level, it was observed that the plant extract showed an effective inhibition (IC50 ) against glutathione S-transferase (GST; 12.84 mM), acetyl cholinesterase (AChE; 15.07 mM), and α-Gly (11.75 mM) enzymes when compared with standard inhibitors. Antioxidant activities of DCM methanol extract were determined via two well-known in vitro techniques. The extracts showed antioxidant activities against the DPPH and ABTS+ . The LC-ESI-MS/MS was used to determine the phenolic compounds of methanol extract from DCM. Chlorogenic acid (2,089.096 µg/g), shikimic acid (193.14 µg/g), and coumarin (113.604 µg/g) were characterized as major phenolic compounds. In addition, the interactions of chlorogenic acid, chrysin, coumarin, and shikimic acid with the used three enzymes have been calculated using molecular docking simulation. PRACTICAL APPLICATIONS: Plant natural phenolic compounds have protective effects such as anti-inflammatory, antioxidant, anticarcinogen, and enzyme inhibitory. Therefore, it has an important place in the food and pharmaceutical industry. The present study aims to reveal the enzyme inhibitory, antioxidant, and anticarcinogenic properties of the Daucus carota ssp. Major (DCM) plant extract. Significant results were obtained against the PC3 cells compared to normal PNT1a prostate epithelial cells. DCM extract demonstrated considerable antioxidant activity and inhibitory potential on used metabolic enzymes. These biological effects are thought to have a relationship with rich chemical composition.
Assuntos
Acetilcolinesterase , Daucus carota , Glutationa Transferase , Glicosídeo Hidrolases , Humanos , Masculino , Simulação de Acoplamento Molecular , Células PC-3 , Compostos Fitoquímicos , Extratos Vegetais/farmacologia , Próstata , Espectrometria de Massas em TandemRESUMO
Prostate cancer is the most frequently diagnosed tumor in men and the second leading cause of cancer-associated mortality in most developed countries. 3,5-Diaryl substituted pyrazole derivatives (20-28) were prepared starting from related chalcones and biologically evaluated for in vitro growth inhibition activity against PC3 and DU145 human prostate cancer cell lines. Compounds 23, 26, and 28 were found to be more potent as compared to the other halogen-substituted derivatives. Especially, the 2-bromo-substituted pyrazole derivative (26) was found to be more potent against PC3 and DU145 cells. Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor 2 (VEGFR2) are known to be expressed in DU145 and PC3 cancer cells. The binding mode of the most selective compound 26 toward EGFR and VEGFR2 was investigated by employing docking simulations based on GLIDE standard precision (-5.912 and -6.949 kcal/mol, respectively).
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Pirazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Receptores ErbB/metabolismo , Humanos , Masculino , Simulação de Acoplamento Molecular , Células PC-3 , Neoplasias da Próstata/patologia , Pirazóis/síntese química , Pirazóis/química , Relação Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio VascularRESUMO
BACKGROUND: Prostate cancer (PCa) is the most common visceral malignancy and the second leading cause of cancer deaths in US men. The two most common genetic alterations in PCa are expression of the TMPRSS2/ERG (TE) fusion gene and loss of the PTEN tumor suppressor. These genetic alterations act cooperatively to transform prostatic epithelium but the exact mechanisms involved are unclear. METHODS: Microarray expression analysis of immortalized prostate epithelial cells transformed by loss of PTEN and expression of the TE fusion revealed MEX3D as one of the most highly upregulated genes. MEX3D expression in prostate cancer was examined in patient samples and in silico. In vitro and in vivo studies to characterize the biological impact of MEX3D were carried out. Analysis of the TCGA PanCancer database revealed TCF3 as a major target of MEX3D. The induction of TCF3 by MEX3D was confirmed and the biological impact of TCF3 examined by in vitro studies. RESULTS: MEX3D is expressed at increased levels in prostate cancer and is increased by decreased PTEN and/or expression of the TE fusion gene and drives soft agar colony formation, invasion and tumor formation in vivo. The known oncogenic transcription factor TCF3 is highly correlated with MEX3D in prostate cancer. MEX3D expression strongly induces TCF3, which promotes soft agar colony formation and invasion in vitro. CONCLUSIONS: Loss of PTEN and expression of the TE fusion gene in prostate cancer strongly upregulates expression of MEX3D and its target TCF3 and promotes transformation associated phenotypes via this pathway.