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1.
Molecules ; 26(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34201944

RESUMO

Photodynamic therapy (PDT) as a safe, non-invasive modality for cancer therapy, in which the low oxygen and high glutathione in the tumor microenvironment reduces therapeutic efficiency. In order to overcome these problems, we prepared a supramolecular photosensitive system of O2-Cu/ZIF-8@ZIF-8@WP6-MB (OCZWM), which was loaded with oxygen to increase the oxygen concentration in the tumor microenvironment, and the Cu2+ in the system reacted with glutathione (GSH) to reduce the GSH concentration to generate Cu+. It is worth noting that the generated Cu+ can produce the Fenton reaction, thus realizing the combination therapy of PDT and chemodynamic therapy (CDT) to achieve the purpose of significantly improving the anti-cancer efficiency.


Assuntos
Neoplasias/tratamento farmacológico , Fotoquimioterapia , Fármacos Fotossensibilizantes , Microambiente Tumoral/efeitos dos fármacos , Células Hep G2 , Humanos , Azul de Metileno/química , Neoplasias/metabolismo , Neoplasias/patologia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Compostos de Amônio Quaternário/química
2.
Molecules ; 26(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202245

RESUMO

Cancer-based magnetic theranostics has gained significant interest in recent years and can contribute as an influential archetype in the effective treatment of cancer. Owing to their excellent biocompatibility, minute sizes and reactive functional surface groups, magnetic nanoparticles (MNPs) are being explored as potential drug delivery systems. In this study, MgFe2O4 ferrite MNPs were evaluated for their potential to augment the delivery of the anticancer drug doxorubicin (DOX). These MNPs were successfully synthesized by the glycol-thermal method and functionalized with the polymers; chitosan (CHI), polyvinyl alcohol (PVA) and polyethylene glycol (PEG), respectively, as confirmed by Fourier transform infrared (FTIR) spectroscopy. X-ray diffraction (XRD) confirmed the formation of the single-phase cubic spinel structures while vibrating sample magnetometer (VSM) analysis confirmed the superparamagnetic properties of all MNPs. Transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA) revealed small, compact structures with good colloidal stability. CHI-MNPs had the highest DOX encapsulation (84.28%), with the PVA-MNPs recording the lowest encapsulation efficiency (59.49%). The 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide (MTT) cytotoxicity assays conducted in the human embryonic kidney (HEK293), colorectal adenocarcinoma (Caco-2), and breast adenocarcinoma (SKBR-3) cell lines showed that all the drug-free polymerized MNPs promoted cell survival, while the DOX loaded MNPs significantly reduced cell viability in a dose-dependent manner. The DOX-CHI-MNPs possessed superior anticancer activity (<40% cell viability), with approximately 85.86% of the drug released after 72 h in a pH-responsive manner. These MNPs have shown good potential in enhancing drug delivery, thus warranting further optimizations and investigations.


Assuntos
Antibióticos Antineoplásicos , Doxorrubicina , Portadores de Fármacos , Nanopartículas de Magnetita , Neoplasias/tratamento farmacológico , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/farmacologia , Células CACO-2 , Quitosana/química , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Compostos Férricos/química , Células HEK293 , Humanos , Nanopartículas de Magnetita/química , Nanopartículas de Magnetita/uso terapêutico , Neoplasias/metabolismo , Neoplasias/patologia , Polietilenoglicóis/química , Álcool de Polivinil/química
3.
Molecules ; 26(13)2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34203547

RESUMO

The effect of enhanced permeability and retention is often not sufficient for highly effective cancer therapy with nanoparticles, and the development of active targeted drug delivery systems based on nanoparticles is probably the main direction of modern cancer medicine. To meet the challenge, we developed polymer PLGA nanoparticles loaded with fluorescent photosensitive xanthene dye, Rose Bengal, and decorated with HER2-recognizing artificial scaffold protein, affibody ZHER2:342. The obtained 170 nm PLGA nanoparticles possess both fluorescent and photosensitive properties. Namely, under irradiation with the green light of 540 nm nanoparticles, they produced reactive oxygen species leading to cancer cell death. The chemical conjugation of PLGA with anti-HER2 affibody resulted in the selective binding of nanoparticles only to HER2-overexpressing cancer cells. HER2 is a receptor tyrosine kinase that belongs to the EGFR/ERbB family and is overexpressed in 30% of breast cancers, thus serving as a clinically relevant oncomarker. However, the standard targeting molecules such as full-size antibodies possess serious drawbacks, such as high immunogenicity and the need for mammalian cell production. We believe that the developed affibody-decorated targeted photosensitive PLGA nanoparticles will provide new solutions for ongoing problems in cancer diagnostics and treatment, as well in cancer theranostics.


Assuntos
Sistemas de Liberação de Medicamentos , Nanopartículas , Neoplasias/terapia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Receptor ErbB-2/metabolismo , Proteínas Recombinantes de Fusão , Células A549 , Animais , Células CHO , Morte Celular/efeitos dos fármacos , Cricetulus , Humanos , Nanopartículas/química , Nanopartículas/uso terapêutico , Neoplasias/metabolismo , Neoplasias/patologia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/farmacologia , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/farmacologia
4.
Int J Mol Sci ; 22(11)2021 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-34204103

RESUMO

Research on the neurobiology of cancer, which lies at the border of neuroscience and oncology, has elucidated the mechanisms and pathways that enable the nervous system to modulate processes associated with cancer initiation and progression. This research has also shown that several drugs which modulate interactions between the nervous system and the tumor micro- and macroenvironments significantly reduced the progression of cancer in animal models. Encouraging results were also provided by prospective clinical trials investigating the effect of drugs that reduce adrenergic signaling on the course of cancer in oncological patients. Moreover, it has been shown that reducing adrenergic signaling might also reduce the incidence of cancer in animal models, as well as in humans. However, even if many experimental and clinical findings have confirmed the preventive and therapeutic potential of drugs that reduce the stimulatory effect of the nervous system on processes related to cancer initiation and progression, several questions remain unanswered. Therefore, the aim of this review is to critically evaluate the efficiency of these drugs and to discuss questions that need to be answered before their introduction into conventional cancer treatment and prevention.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/prevenção & controle , Animais , Antineoplásicos/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Progressão da Doença , Humanos , Microbiota/efeitos dos fármacos , Neoplasias/patologia , Transdução de Sinais/efeitos dos fármacos
5.
Molecules ; 26(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209621

RESUMO

Silica nanoparticles (SiO2 NPs) synthesized by the Stober method were used as drug delivery vehicles. Doxorubicin hydrochloride (DOX·HCl) is a chemo-drug absorbed onto the SiO2 NPs surfaces. The DOX·HCl loading onto and release from the SiO2 NPs was monitored via UV-VIS and fluorescence spectra. Alternatively, the zeta potential was also used to monitor and evaluate the DOX·HCl loading process. The results showed that nearly 98% of DOX·HCl was effectively loaded onto the SiO2 NPs' surfaces by electrostatic interaction. The pH-dependence of the process wherein DOX·HCl release out of DOX·HCl-SiO2 NPs was investigated as well. For comparison, both the free DOX·HCl molecules and DOX·HCl-SiO2 NPs were used as the labels for cultured cancer cells. Confocal laser scanning microscopy images showed that the DOX·HCl-SiO2 NPs were better delivered to cancer cells which are more acidic than healthy cells. We propose that engineered DOX·HCl-SiO2 systems are good candidates for drug delivery and clinical applications.


Assuntos
Antineoplásicos , Doxorrubicina , Portadores de Fármacos , Nanopartículas , Neoplasias , Dióxido de Silício , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Humanos , Células MCF-7 , Microscopia Confocal , Nanopartículas/química , Nanopartículas/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Dióxido de Silício/química , Dióxido de Silício/farmacocinética , Dióxido de Silício/farmacologia
6.
Isr Med Assoc J ; 23(7): 426-431, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34251125

RESUMO

BACKGROUND: Decisions on medication treatment in children dying from cancer are often complex and may result in polypharmacy and increased medication burden. There is no information on medication burden in pediatric cancer patients at the end of life (EOL). OBJECTIVES: To characterize medication burden during the last hospitalization in children dying from cancer. METHODS: We performed a retrospective cohort study based on medical records of 90 children who died from cancer in hospital between 01 January 2010 and 30 December 2018. Demographic and clinical information were collected for the last hospitalization. We compared medication burden (number of medication orders) at hospitalization and at time of death and examined whether changes in medication burden were associated with clinical and demographic parameters. RESULTS: Median medication burden was higher in leukemia/lymphoma patients (6 orders) compared to solid (4 orders) or CNS tumor patients (4 orders, P = 0.006). Overall, the median number of prescriptions per patient did not change until death (P = 0.42), while there was a significant reduction for some medication subgroups (chemotherapy [P = 0.035], steroids [P = 0.010]).Patients dying in the ICU (n=15) had a higher medication burden at death (6 orders) than patients dying on wards (3 orders, P = 0.001). There was a trend for a reduction in medication burden in patients with "Do not resuscitate" (DNR) orders (P = 0.055). CONCLUSIONS: Polypharmacy is ubiquitous among pediatric oncology patients at EOL. Disease type and DNR status may affect medication burden and deprescribing during the last hospitalization.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias , Cuidados Paliativos , Polimedicação , Esteroides/uso terapêutico , Assistência Terminal , Criança , Procedimentos Clínicos/estatística & dados numéricos , Demografia , Feminino , Pesquisa sobre Serviços de Saúde , Hospitalização/estatística & dados numéricos , Humanos , Israel/epidemiologia , Masculino , Estadiamento de Neoplasias , Neoplasias/tratamento farmacológico , Neoplasias/mortalidade , Neoplasias/patologia , Cuidados Paliativos/métodos , Cuidados Paliativos/estatística & dados numéricos , Ordens quanto à Conduta (Ética Médica) , Assistência Terminal/métodos , Assistência Terminal/estatística & dados numéricos
8.
Int J Mol Sci ; 22(12)2021 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-34202987

RESUMO

Polyphenols are naturally occurring compounds found in abundance in fruits and vegetables. Their health-promoting properties and their use in the prevention and treatment of many human diseases, including cancer, have been known for years. Many anti-cancer drugs are derived from these natural compounds. Etoposide, which is a semi-synthetic derivative of podophyllotoxin, a non-alkaloid lignan isolated from the dried roots and rhizomes of Podophyllum peltatum or Podophyllum emodi (Berberidaceae), is an example of such a compound. In this review, we present data on the effects of polyphenols on the anti-cancer activity of etoposide in in vitro and in vivo studies.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Etoposídeo/farmacologia , Polifenóis/farmacologia , Inibidores da Topoisomerase II/farmacologia , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/uso terapêutico , Biomarcadores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Sinergismo Farmacológico , Etoposídeo/uso terapêutico , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/etiologia , Neoplasias/metabolismo , Neoplasias/patologia , Polifenóis/química , Polifenóis/uso terapêutico , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Int J Mol Sci ; 22(11)2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34200240

RESUMO

The term neuroinflammation refers to inflammation of the nervous tissue, in general, and in the central nervous system (CNS), in particular. It is a driver of neurotoxicity, it is detrimental, and implies that glial cell activation happens prior to neuronal degeneration and, possibly, even causes it. The inflammation-like glial responses may be initiated in response to a variety of cues such as infection, traumatic brain injury, toxic metabolites, or autoimmunity. The inflammatory response of activated microglia engages the immune system and initiates tissue repair. Through translational research the role played by neuroinflammation has been acknowledged in different disease entities. Intriguingly, these entities include both those directly related to the CNS (commonly designated neuropsychiatric disorders) and those not directly related to the CNS (e.g., cancer and diabetes type 2). Interestingly, all the above-mentioned entities belong to the same group of "complex disorders". This review aims to summarize cumulated data supporting the hypothesis that neuroinflammation is a common denominator of a wide variety of complex diseases. We will concentrate on cancer, type 2 diabetes (T2DM), and neuropsychiatric disorders (focusing on mood disorders).


Assuntos
Diabetes Mellitus Tipo 2/etiologia , Inflamação/complicações , Transtornos Mentais/etiologia , Neoplasias/etiologia , Neurônios/patologia , Animais , Diabetes Mellitus Tipo 2/patologia , Humanos , Transtornos Mentais/patologia , Neoplasias/patologia
10.
Int J Mol Sci ; 22(11)2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34200309

RESUMO

Many human cancers exhibit defects in key DNA damage response elements that can render tumors insensitive to the cell death-promoting properties of DNA-damaging therapies. Using agents that directly induce apoptosis by targeting apoptotic components, rather than relying on DNA damage to indirectly stimulate apoptosis of cancer cells, may overcome classical blocks exploited by cancer cells to evade apoptotic cell death. However, there is increasing evidence that cells surviving sublethal exposure to classical apoptotic signaling may recover with newly acquired genomic changes which may have oncogenic potential, and so could theoretically spur the development of subsequent cancers in cured patients. Encouragingly, cells surviving sublethal necroptotic signaling did not acquire mutations, suggesting that necroptosis-inducing anti-cancer drugs may be less likely to trigger therapy-related cancers. We are yet to develop effective direct inducers of other cell death pathways, and as such, data regarding the consequences of cells surviving sublethal stimulation of those pathways are still emerging. This review details the currently known mutagenic consequences of cells surviving different cell death signaling pathways, with implications for potential oncogenic transformation. Understanding the mechanisms of mutagenesis associated (or not) with various cell death pathways will guide us in the development of future therapeutics to minimize therapy-related side effects associated with DNA damage.


Assuntos
Morte Celular , Dano ao DNA , Mutagênese , Mutação , Neoplasias/patologia , Animais , Humanos , Neoplasias/etiologia
11.
Int J Mol Sci ; 22(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200849

RESUMO

Nitric oxide (NO) has been identified and described as a dual mediator in cancer according to dose-, time- and compartment-dependent NO generation. The present review addresses the different epigenetic mechanisms, such as histone modifications and non-coding RNAs (ncRNAs), miRNA and lncRNA, which regulate directly or indirectly nitric oxide synthase (NOS) expression and NO production, impacting all hallmarks of the oncogenic process. Among lncRNA, HEIH and UCA1 develop their oncogenic functions by inhibiting their target miRNAs and consequently reversing the inhibition of NOS and promoting tumor proliferation. The connection between miRNAs and NO is also involved in two important features in cancer, such as the tumor microenvironment that includes key cellular components such as tumor-associated macrophages (TAMs), cancer associated fibroblasts (CAFs) and cancer stem cells (CSCs).


Assuntos
Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Neoplasias/patologia , Células-Tronco Neoplásicas/patologia , Óxido Nítrico/metabolismo , RNA Longo não Codificante/genética , Microambiente Tumoral , Animais , Fibroblastos Associados a Câncer/patologia , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Células-Tronco Neoplásicas/metabolismo , Transdução de Sinais
12.
Int J Mol Sci ; 22(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201047

RESUMO

MYC is a transcription factor that controls the expression of a large fraction of cellular genes linked to cell cycle progression, metabolism and differentiation. MYC deregulation in tumors leads to its pervasive genome-wide binding of both promoters and distal regulatory regions, associated with selective transcriptional control of a large fraction of cellular genes. This pairs with alterations of cell cycle control which drive anticipated S-phase entry and reshape the DNA-replication landscape. Under these circumstances, the fine tuning of DNA replication and transcription becomes critical and may pose an intrinsic liability in MYC-overexpressing cancer cells. Here, we will review the current understanding of how MYC controls DNA and RNA synthesis, discuss evidence of replicative and transcriptional stress induced by MYC and summarize preclinical data supporting the therapeutic potential of triggering replicative stress in MYC-driven tumors.


Assuntos
Replicação do DNA , Regulação da Expressão Gênica , Neoplasias/patologia , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Animais , Dano ao DNA , Humanos , Neoplasias/genética , Neoplasias/metabolismo
13.
Int J Mol Sci ; 22(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201062

RESUMO

Cancer is a disorder of cell growth and proliferation, characterized by different metabolic pathways within normal cells. The Warburg effect is a major metabolic process in cancer cells that affects the cellular responses, such as proliferation and apoptosis. Various signaling factors down/upregulate factors of the glycolysis pathway in cancer cells, and these signaling factors are ubiquitinated/deubiquitinated via the ubiquitin-proteasome system (UPS). Depending on the target protein, DUBs act as both an oncoprotein and a tumor suppressor. Since the degradation of tumor suppressors and stabilization of oncoproteins by either negative regulation by E3 ligases or positive regulation of DUBs, respectively, promote tumorigenesis, it is necessary to suppress these DUBs by applying appropriate inhibitors or small molecules. Therefore, we propose that the DUBs and their inhibitors related to the Warburg effect are potential anticancer targets.


Assuntos
Apoptose , Enzimas Desubiquitinantes/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Ubiquitinação , Efeito Warburg em Oncologia , Animais , Humanos
14.
Int J Mol Sci ; 22(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199667

RESUMO

Nanoparticles (NPs) with a high atomic number (Z) are promising radiosensitizers for cancer therapy. However, the dependence of their efficacy on irradiation conditions is still unclear. In the present work, 11 different metal and metal oxide NPs (from Cu (ZCu = 29) to Bi2O3 (ZBi = 83)) were studied in terms of their ability to enhance the absorbed dose in combination with 237 X-ray spectra generated at a 30-300 kVp voltage using various filtration systems and anode materials. Among the studied high-Z NP materials, gold was the absolute leader by a dose enhancement factor (DEF; up to 2.51), while HfO2 and Ta2O5 were the most versatile because of the largest high-DEF region in coordinates U (voltage) and Eeff (effective energy). Several impacts of the X-ray spectral composition have been noted, as follows: (1) there are radiation sources that correspond to extremely low DEFs for all of the studied NPs, (2) NPs with a lower Z in some cases can equal or overcome by the DEF value the high-Z NPs, and (3) the change in the X-ray spectrum caused by a beam passing through the matter can significantly affect the DEF. All of these findings indicate the important role of carefully planning radiation exposure in the presence of high-Z NPs.


Assuntos
Cobre/uso terapêutico , Nanopartículas Metálicas/uso terapêutico , Neoplasias/radioterapia , Radiossensibilizantes/uso terapêutico , Bismuto/química , Bismuto/uso terapêutico , Cobre/química , Relação Dose-Resposta a Droga , Humanos , Nanopartículas Metálicas/química , Método de Monte Carlo , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Óxidos/química , Óxidos/uso terapêutico , Radiossensibilizantes/química , Dosagem Radioterapêutica
15.
BMC Infect Dis ; 21(1): 636, 2021 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-34215207

RESUMO

BACKGROUND: This study aimed to investigate the epidemiology, microbiology, and risk factors associated with mortality and multi-drug resistance bacterial bloodstream infections (BSIs) among adult cancer patients in Shiraz, Iran. We also report a four-year trend of antimicrobial resistance patterns of BSIs. METHODS: We conducted a retrospective study at a referral oncology hospital from July 2015 to August 2019, which included all adults with confirmed BSI. RESULTS: 2393 blood cultures tested during the four-year study period; 414 positive cultures were included. The mean age of our patients was 47.57 ± 17.46 years old. Central Line-Associated BSI (CLABSI) was more common in solid tumors than patients with hematological malignancies. Gram-negative (GN) bacteria were more detected (63.3%, 262) than gram-positive bacteria (36.7%, 152). Escherichia coli was the most common gram-negative organism (123/262, 47%), followed by Pseudomonas spp. (82/262, 31%) and Klebsiella pneumoniae (38/262, 14.5%). Coagulase-negative staphylococci (CoNS) was the most frequently isolated pathogen among gram-positive bacteria (83/152, 54.6%). Acinetobacter spp., Pseudomonas spp., E. coli, and K. pneumoniae were the most common Extended-Spectrum Beta-Lactamase (ESBL) producers (100, 96.2, 66.7%, and 60.7, respectively). Acinetobacter spp., Pseudomonas spp., Enterobacter spp., E. coli, and K. pneumoniae were the most common carbapenem-resistant (CR) isolates (77.8, 70.7, 33.3, 24.4, and 13.2%, respectively). Out of 257 Enterobacterales and non-fermenter gram-negative BSIs, 39.3% (101/257) were carbapenem-resistant. Although the incidence of multi-drug resistance (MDR) gram-negative BSI increased annually during 2015-2018, the mortality rate of gram-negative BSI remains unchanged at about 20% (p-value = 0.55); however, the mortality rate was significantly greater (35.4%) in those with resistant gram-positive BSI (p-value = 0.001). The overall mortality rate was 21.5%. Early (7-day mortality) and late mortality rate (30-day mortality) were 10 and 3.4%, respectively. CONCLUSIONS: The emergence of MDR gram-negative BSI is a significant healthcare problem in oncology centers. The high proportion of the most frequently isolated pathogens were CR and ESBL-producing Enterobacterales and Pseudomonas spp. We have few effective choices against MDRGN BSI, especially in high-risk cancer patients, which necessitate newer treatment options.


Assuntos
Bacteriemia/complicações , Bactérias/patogenicidade , Farmacorresistência Bacteriana , Resistência a Múltiplos Medicamentos , Neoplasias/mortalidade , Sepse/complicações , Bacteriemia/microbiologia , Bactérias/isolamento & purificação , Terapia Combinada , Feminino , Humanos , Irã (Geográfico)/epidemiologia , Klebsiella pneumoniae/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Neoplasias/etiologia , Neoplasias/patologia , Estudos Retrospectivos , Fatores de Risco , Sepse/microbiologia
16.
Molecules ; 26(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202711

RESUMO

Cancer is a multifactorial disease that may be tackled by targeting different signaling pathways. Heme oxygenase-1 (HO-1) and sigma receptors (σRs) are both overexpressed in different human cancers, including prostate and brain, contributing to the cancer spreading. In the present study, we investigated whether HO-1 inhibitors and σR ligands, as well a combination of the two, may influence DU145 human prostate and U87MG human glioblastoma cancer cells proliferation. In addition, we synthesized, characterized, and tested a small series of novel hybrid compounds (HO-1/σRs) 1-4 containing the chemical features needed for HO-1 inhibition and σR modulation. Herein, we report for the first time that targeting simultaneously HO-1 and σR proteins may be a good strategy to achieve increased antiproliferative activity against DU145 and U87MG cells, with respect to the mono administration of the parent compounds. The obtained outcomes provide an initial proof of concept useful to further optimize the structure of HO-1/σRs hybrids to develop novel potential anticancer agents.


Assuntos
Antineoplásicos , Inibidores Enzimáticos , Heme Oxigenase-1/antagonistas & inibidores , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias , Receptores sigma/antagonistas & inibidores , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Heme Oxigenase-1/metabolismo , Humanos , Proteínas de Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Ratos , Receptores sigma/metabolismo
17.
Molecules ; 26(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202721

RESUMO

Marine natural products are abundant resources for antioxidants, but the antioxidant property of the soft corals-derived sinularin and dihydrosinularin were unknown. This study aimed to assess antioxidant potential and antiproliferation effects of above compounds on cancer cells, and to investigate the possible relationships between them. Results show that sinularin and dihydrosinularin promptly reacted with 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2-azinobis (3-ethyl-benzothiazoline-6-sulfonic acid) (ABTS), and hydroxyl (•OH), demonstrating a general radical scavenger activity. Sinularin and dihydrosinularin also show an induction for Fe+3-reduction and Fe+2-chelating capacity which both strengthen their antioxidant activities. Importantly, sinularin shows higher antioxidant properties than dihydrosinularin. Moreover, 24 h ATP assays show that sinularin leads to higher antiproliferation of breast, lung, and liver cancer cells than dihydrosinularin. Therefore, the differential antioxidant properties of sinularin and dihydrosinularin may contribute to their differential anti-proliferation of different cancer cells.


Assuntos
Antozoários/química , Antineoplásicos , Antioxidantes , Diterpenos , Compostos Heterocíclicos com 3 Anéis , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Antioxidantes/química , Antioxidantes/isolamento & purificação , Antioxidantes/farmacologia , Linhagem Celular Tumoral , Diterpenos/química , Diterpenos/isolamento & purificação , Diterpenos/farmacologia , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/isolamento & purificação , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Neoplasias/metabolismo , Neoplasias/patologia
18.
Molecules ; 26(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202760

RESUMO

A phytochemical investigation of the leaves of the medicinal plant Isodon rubescens led to the isolation of the two new degraded abietane lactone diterpenoids rubesanolides F (1) and G (2). Their structures were elucidated based on the analyses of the HRESIMS and 1D/2D NMR spectral data, and their absolute configurations were determined by ECD spectrum calculations and X-ray single crystal diffraction methods. Compounds 1 and 2, with a unique γ-lactone subgroup between C-8 and C-20, were found to form a carbonyl carbon at C-13 by removal of the isopropyl group in an abietane diterpene skeleton. Rubesanolide G (2) is a rare case of abietane that possesses a cis-fused configuration between rings B and C. The two isolates were evaluated for their biological activities against two cancer cell lines (A549 and HL60), three fungal strains (Candida alba, Aspergillus niger and Rhizopus nigricans) and three bacterial strains (Escherichia coli, Staphylococcus aureus and Bacillus subtilis).


Assuntos
Abietanos , Anti-Infecciosos , Antineoplásicos Fitogênicos , Bactérias/crescimento & desenvolvimento , Fungos/crescimento & desenvolvimento , Isodon/química , Lactonas , Neoplasias/tratamento farmacológico , Folhas de Planta/química , Células A549 , Abietanos/química , Abietanos/isolamento & purificação , Abietanos/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/isolamento & purificação , Anti-Infecciosos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Células HL-60 , Humanos , Lactonas/química , Lactonas/isolamento & purificação , Lactonas/farmacologia , Neoplasias/metabolismo , Neoplasias/patologia
19.
Int J Mol Sci ; 22(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207286

RESUMO

Rather than primary solid tumors, metastasis is one of the hallmarks of most cancer deaths. Metastasis is a multistage event in which cancer cells escape from the primary tumor survive in the circulation and disseminate to distant sites. According to Stephen Paget's "Seed and Soil" hypothesis, metastatic capacity is determined not only by the internal oncogenic driving force but also by the external environment of tumor cells. Throughout the body, macrophages are required for maintaining tissue homeostasis, even in the tumor milieu. To fulfill these multiple functions, macrophages are polarized from the inflammation status (M1-like) to anti-inflammation status (M2-like) to maintain the balance between inflammation and regeneration. However, tumor cell-enforced tumor-associated macrophages (TAMs) (a high M2/M1 ratio status) are associated with poor prognosis for most solid tumors, such as ovarian cancer. In fact, clinical evidence has verified that TAMs, representing up to 50% of the tumor mass, exert both protumor and immunosuppressive effects in promoting tumor metastasis through secretion of interleukin 10 (IL10), transforming growth factor ß (TGFß), and VEGF, expression of PD-1 and consumption of arginine to inhibit T cell anti-tumor function. However, the underlying molecular mechanisms by which the tumor microenvironment favors reprogramming of macrophages to TAMs to establish a premetastatic niche remain controversial. In this review, we examine the latest investigations of TAMs during tumor development, the microenvironmental factors involved in macrophage polarization, and the mechanisms of TAM-mediated tumor metastasis. We hope to dissect the critical roles of TAMs in tumor metastasis, and the potential applications of TAM-targeted therapeutic strategies in cancer treatment are discussed.


Assuntos
Neoplasias/patologia , Microambiente Tumoral , Macrófagos Associados a Tumor/imunologia , Animais , Diferenciação Celular , Humanos , Imunoterapia/métodos , Metástase Neoplásica , Neoplasias/imunologia , Neoplasias/terapia , Macrófagos Associados a Tumor/patologia
20.
Nat Commun ; 12(1): 4300, 2021 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-34262035

RESUMO

Common fragile sites (CFSs) are specific breakage-prone genomic regions and are present frequently in cancer cells. The (E2-independent) E3 ubiquitin-conjugating enzyme FATS (fragile site-associated tumor suppressor) has antitumor activity in cancer cells, but the function of FATS in immune cells is unknown. Here, we report a function of FATS in tumor development via regulation of tumor immunity. Fats-/- mice show reduced subcutaneous B16 melanoma and H7 pancreatic tumor growth compared with WT controls. The reduced tumor growth in Fats-/- mice is macrophage dependent and is associated with a phenotypic shift of macrophages within the tumor from tumor-promoting M2-like to antitumor M1-like macrophages. In addition, FATS deficiency promotes M1 polarization by stimulating and prolonging NF-κB activation by disrupting NF-κB/IκBα negative feedback loops and indirectly enhances both CD4+ T helper type 1 (Th1) and cytotoxic T lymphocyte (CTL) adaptive immune responses to promote tumor regression. Notably, transfer of Fats-/- macrophages protects mice against B16 melanoma. Together, these data suggest that FATS functions as an immune regulator and is a potential target in cancer immunotherapy.


Assuntos
Macrófagos/imunologia , Neoplasias/imunologia , Proteínas Supressoras de Tumor/imunologia , Animais , Linhagem Celular Tumoral , Humanos , Imunoterapia , Ativação de Macrófagos , Camundongos , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , Neoplasias/patologia , Neoplasias/terapia , Transdução de Sinais/imunologia , Linfócitos T Citotóxicos/imunologia , Células Th1/imunologia , Proteínas Supressoras de Tumor/deficiência
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