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1.
Cancer Commun (Lond) ; 44(1): 101-126, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-38140698

RESUMO

BACKGROUND: The cellular tumor protein p53 (TP53) is a tumor suppressor gene that is frequently mutated in human cancers. Among various cancer types, the very aggressive high-grade serous ovarian carcinoma (HGSOC) exhibits the highest prevalence of TP53 mutations, present in >96% of cases. Despite intensive efforts to reactivate p53, no clinical drug has been approved to rescue p53 function. In this study, our primary objective was to administer in vitro-transcribed (IVT) wild-type (WT) p53-mRNA to HGSOC cell lines, primary cells, and orthotopic mouse models, with the aim of exploring its impact on inhibiting tumor growth and dissemination, both in vitro and in vivo. METHODS: To restore the activity of p53, WT p53 was exogenously expressed in HGSOC cell lines using a mammalian vector system. Moreover, IVT WT p53 mRNA was delivered into different HGSOC model systems (primary cells and patient-derived organoids) using liposomes and studied for proliferation, cell cycle progression, apoptosis, colony formation, and chromosomal instability. Transcriptomic alterations induced by p53 mRNA were analyzed using RNA sequencing in OVCAR-8 and primary HGSOC cells, followed by ingenuity pathway analysis. In vivo effects on tumor growth and metastasis were studied using orthotopic xenografts and metastatic intraperitoneal mouse models. RESULTS: Reactivation of the TP53 tumor suppressor gene was explored in different HGSOC model systems using newly designed IVT mRNA-based methods. The introduction of WT p53 mRNA triggered dose-dependent apoptosis, cell cycle arrest, and potent long-lasting inhibition of HGSOC cell proliferation. Transcriptome analysis of OVCAR-8 cells upon mRNA-based p53 reactivation revealed significant alterations in gene expression related to p53 signaling, such as apoptosis, cell cycle regulation, and DNA damage. Restoring p53 function concurrently reduces chromosomal instability within the HGSOC cells, underscoring its crucial contribution in safeguarding genomic integrity by moderating the baseline occurrence of double-strand breaks arising from replication stress. Furthermore, in various mouse models, treatment with p53 mRNA reduced tumor growth and inhibited tumor cell dissemination in the peritoneal cavity in a dose-dependent manner. CONCLUSIONS: The IVT mRNA-based reactivation of p53 holds promise as a potential therapeutic strategy for HGSOC, providing valuable insights into the molecular mechanisms underlying p53 function and its relevance in ovarian cancer treatment.


Assuntos
Neoplasias Ovarianas , Proteína Supressora de Tumor p53 , Animais , Camundongos , Humanos , Feminino , Proteína Supressora de Tumor p53/genética , RNA Mensageiro/genética , Gradação de Tumores , Linhagem Celular Tumoral , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Instabilidade Cromossômica , Mamíferos
2.
Neurosci Lett ; 698: 133-139, 2019 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-30641110

RESUMO

Continuous use of crack induces hyperalgesia which is related to drug tolerance. Despite cumulative evidence based on the growth rate of crack abuse, no serious study has been focused on the mechanisms of crack-induced hyperalgesia. This study aimed to elucidate whether extracellular signal-regulated kinases (Erk1/2)/ß-arrestin pathways are involved in the crack-induced hyperalgesia. Fifty adult male Wistar rats were randomly divided into five groups: normal saline (NS), crack (0.9 mg/kg/day), heroin (1 mg/kg/day), crack + barbadin (100 µM), and heroin + barbadin groups, which received their intraperitoneal (i.p) treatments for four weeks. The thermal sensitivity was assessed using the hot-plate test. Moreover, phosphorylation of the Erk1/2 and JNK, as well as expression of protein kinase C-alpha (PKC-α), Mu-receptor (MOR), and ß-arrestin 2 were determined in the whole lysate and membrane fraction using immunoblotting assay in the periaqueductal gray (PAG) area. The results demonstrated that chronic administration of crack and heroin significantly decreased hind-paw withdrawal latency compared to the NS group. Furthermore, crack as well as heroin administration increased phosphorylated Erk1/2 and JNK in the PAG. In addition, membrane ß-arrestin 2 and PKC-α were significantly increased in the crack and heroin-received groups, while membrane MOR expression was decreased in the PAG. Nevertheless, co-administration of barbadin, an inhibitor of ß-arrestin, and crack or heroin reversed all these changes. Our findings may partially confirm the role of ß-arrestin 2 and PKC rearrangements, Erk1/2 and JNK phosphorylation in crack-induced hyperalgesia and provide potential therapeutic targets to attenuate crack-induced hyperalgesia.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/efeitos dos fármacos , Heroína/farmacologia , Hiperalgesia/induzido quimicamente , Substância Cinzenta Periaquedutal/efeitos dos fármacos , beta-Arrestina 2/metabolismo , Animais , Tolerância a Medicamentos/fisiologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Masculino , Morfina/farmacologia , Substância Cinzenta Periaquedutal/metabolismo , Ratos Wistar , Receptores Opioides mu/efeitos dos fármacos , Receptores Opioides mu/metabolismo
3.
Brain Res ; 1692: 100-109, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29787771

RESUMO

Mitochondria involve in the determination of ischemic neuronal cell fate through regulation of apoptotic and necrotic cell death. Phosphatase and tensin homolog (PTEN) protein negatively regulates Akt/PKB signaling which is the major cell survival pathway. The current study aimed to examine the impact of SF1670, a potent PTEN inhibitor, on mitochondria-mediated cell survival pathways in an in vitro stroke-like model. PC12 cells were exposed to one hour oxygen and glucose deprivation (OGD) followed by different time points of reperfusion (0, 30, 60, 120 and 180 min) and SF1670 treatments. Our findings showed that OGD/R exposure increased reactive oxygen species (ROS) levels, reduced phosphorylated Akt (p-Akt), ratios of Bcl-2/BAX, intracellular ATP, mitochondrial vital activity and mitochondrial membrane potential (Δψm). OGD/R exposure also increased cleaved caspase 3/pro-caspase 3 and cleaved caspase 9/pro-caspase 9 ratios associated with low cell viability, high lactate dehydrogenase (LDH) release, and greater apoptotic cell death in the TUNEL assay. Conversely, inhibition of PTEN by SF1670 were associated with increased expression of p-Akt and anti-apoptotic proteins (Bcl-2), attenuated pro-apoptotic proteins (BAX) and oxidative stress index (ROS), improved mitochondrial function (restored MMP and ATP), and decreased apoptotic cell death. These results strongly suggest that neuroprotective effect of SF1670 against OGD/R-induced cell death at least is partially mediated through mitoprotective properties of SF1670.


Assuntos
Glucose/deficiência , Oxigênio/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Caspase 3/metabolismo , Caspase 9/metabolismo , Morte Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Marcação In Situ das Extremidades Cortadas , L-Lactato Desidrogenase/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Células PC12 , PTEN Fosfo-Hidrolase/antagonistas & inibidores , Fenantrenos/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Fatores de Tempo , Proteína X Associada a bcl-2/metabolismo
4.
Artif Cells Nanomed Biotechnol ; 45(6): 1-11, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27632797

RESUMO

Cancer is a main public health problem that is known as a malignant tumor and out-of-control cell growth, with the potential to assault or spread to other parts of the body. Recently, remarkable efforts have been devoted to develop nanotechnology to improve the delivery of anticancer drug to tumor tissue as minimizing its distribution and toxicity in healthy tissue. Nanotechnology has been extensively used in the advance of new strategies for drug delivery and cancer therapy. Compared to customary drug delivery systems, nano-based drug delivery method has greater potential in different areas, like multiple targeting functionalization, in vivo imaging, extended circulation time, systemic control release, and combined drug delivery. Nanofibers are used for different medical applications such as drug delivery systems.


Assuntos
Antineoplásicos , Sistemas de Liberação de Medicamentos/métodos , Nanoestruturas , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Humanos , Nanoestruturas/química , Nanoestruturas/uso terapêutico , Neoplasias/metabolismo , Neoplasias/patologia
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