RESUMO
BACKGROUND: Metformin, a widely prescribed antidiabetic drug, has shown several promising effects for cancer treatment. These effects have been shown to be mediated by dual modulation of the AMPK-mTORC1 axis, where AMPK acts upstream of mTORC1 to decrease its activity. Nevertheless, alternative pathways have been recently discovered suggesting that metformin can act through of different targets regulation. METHODS: We performed a transcriptome screening analysis using HeLa xenograft tumors generated in NOD-SCID mice treated with or without metformin to examine genes regulated by metformin. Western Blot analysis, Immunohistochemical staining, and RT-qPCR were used to confirm alterations in gene expression. The TNMplot and GEPIA2 platform were used for in silico analysis of genes found up-regulated by metformin, in cervical cancer patients. We performed an AMPK knock-down using AMPK-targeted siRNAs and mTOR inhibition with rapamycin to investigate the molecular mechanisms underlying the effect of metformin in cervical cancer cell lines. RESULTS: We shown that metformin decreases tumor growth and increased the expression of a group of antitumoral genes involved in DNA-binding transcription activator activity, hormonal response, and Dcp1-Dcp2 mRNA-decapping complex. We demonstrated that ZFP36 could act as a new molecular target increased by metformin. mTORC1 inhibition using rapamycin induces ZFP36 expression, which could suggest that metformin increases ZFP36 expression and requires mTORC1 inhibition for such effect. Surprisingly, in HeLa cells AMPK inhibition did not affect ZFP36 expression, suggesting that additional signal transducers related to suppressing mTORC1 activity, could be involved. CONCLUSIONS: These results highlight the importance of ZFP36 activation in response to metformin treatment involving mTORC1 inhibition.
Assuntos
Alvo Mecanístico do Complexo 1 de Rapamicina , Metformina , Neoplasias do Colo do Útero , Ensaios Antitumorais Modelo de Xenoenxerto , Humanos , Metformina/farmacologia , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/genética , Feminino , Animais , Camundongos , Células HeLa , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Camundongos SCID , Camundongos Endogâmicos NOD , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Transdução de Sinais/efeitos dos fármacos , Sirolimo/farmacologiaRESUMO
OBJECTIVE: This systematic review and meta-analysis aimed to investigate the effects of herbal treatments on cervicovaginal human papillomavirus infection. METHODS: A comprehensive literature search was conducted in PubMed, Scopus, Science Direct, and the Cochrane Library until December 2023, following Cochrane guidelines. Data were analyzed using the Review Manager computer program (Version 5.4.1). RESULTS: Five randomized controlled trials involving a total sample size of 662 women were included in the study. The pooled odds ratio for individuals testing negative for human papillomavirus after herbal intervention among human papillomavirus-positive patients was 1.86 (95% confidence interval (CI) 0.64-5.43), according to the fixed-effects model. Three out of the five studies indicated a significant relationship. The relationship between positive human papillomavirus infection and herbal treatments, measured by the fixed-effects model, resulted in a pooled odds ratio of 0.41 (95%CI 0.17-1.01), reporting a significant association (p=0.05). Subgroup analysis revealed a significant reduction in the relationship between herbal treatment and atypical squamous cells of undetermined significance (OR 0.16, 95%CI 0.03-0.88, p=0.04) but no significant impact on the relationship between herbal treatment and low-grade squamous intraepithelial lesion (OR 0.33, 95%CI 0.01-8.77, p=0.51). CONCLUSION: The meta-analysis suggests that herbal treatments reduce human papillomavirus infections. While herbal treatments show a significant reduction in atypical squamous cells of undetermined significance, they do not significantly impact the regression of low-grade squamous intraepithelial lesions.
Assuntos
Infecções por Papillomavirus , Humanos , Feminino , Infecções por Papillomavirus/tratamento farmacológico , Fitoterapia/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias do Colo do Útero/virologia , Neoplasias do Colo do Útero/tratamento farmacológicoRESUMO
OBJECTIVE: Cancer genomics and transcriptomics studies have provided a large volume of data that enables to test of hypotheses based on real data from cancer patients. Ezrin (encoded by the EZR gene) is a highly expressed protein in cancer that contributes to linking the actin cytoskeleton to the cell membrane and signal transduction pathways involved in oncogenesis and disease progression. NSC305787 is a pharmacological ezrin inhibitor with potential antineoplastic effects. In the present study, the authors prospected EZR mRNA levels in a pan-cancer analysis and identified potential cancers that could benefit from anti-EZR therapies. METHODS: This study analyzed TCGA data for 32 cancer types, emphasizing cervical squamous cell carcinoma and stomach adenocarcinoma. It investigated the impact of EZR transcript levels on clinical outcomes and identified differentially expressed genes. Cell lines were treated with NSC305787, and its effects were assessed through various cellular and molecular assays. RESULTS: EZR mRNA levels are highly expressed, and their expression is associated with biologically relevant molecular processes in cervical squamous carcinoma and stomach adenocarcinoma. In cellular models of cervical and gastric cancer, NSC305787 reduces cell viability and clonal growth (p < 0.05). Molecular analyses indicate that the pharmacological inhibition of EZR induces molecular markers of cell death and DNA damage, in addition, to promoting the expression of genes associated with apoptosis and inhibiting the expression of genes related to survival and proliferation. CONCLUSION: The present findings provide promising evidence that ezrin may be a molecular target in the treatment of cervical and gastric carcinoma.
Assuntos
Adenocarcinoma , Proteínas do Citoesqueleto , Perfilação da Expressão Gênica , Neoplasias Gástricas , Neoplasias do Colo do Útero , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Neoplasias Gástricas/metabolismo , Proteínas do Citoesqueleto/genética , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/metabolismo , Linhagem Celular Tumoral , Feminino , Adenocarcinoma/genética , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Adenocarcinoma/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , RNA Mensageiro , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Apoptose/genéticaRESUMO
T agetes patula , known as French Marigold, belongs to the family Asteraceae. Human papillomavirus infection is considered one of the causes of cervical cancer. This study assessed the cytotoxic activity and intracellular oxidative capacity of compounds isolated from extract of T. patula flowers as anti - cancer cervical agents. Fraction F6 of n - butanol extract was subjected to column chromatography and HPLC - ESI - MS. The isolated compo unds of T. patula were used to examine cytotoxic activity and the production of total reactive oxygen species in SiHa and HeLa cells; the cells were also characterized using scanning electron microscopy. Patulitrin was cytotoxic to SiHa and HeLa cells. An increase in ROS production was observed at different times of treatment of cells with patuletin and patulitrin. Scanning electron microscopy showed morphological changes in SiHa and HeLa cells. Thus, compounds isolated from T. patula have great treatment p otential against cervical cancer.
Tagetes patula , conocida como cempasúchil francés, pertenece a la familia Asteraceae. La infección por el virus del papiloma humano se considera una de las causas del cáncer cervical. En este estudio, se evaluó la actividad citotóxica y la capacidad oxidativa intracelular de los compuestos aislados del extracto de las flores de T. patula como agentes anticancerígenos cervicales. La fracción F6 del ext racto de n - butanol se sometió a cromatografía en columna y HPLC - ESI - MS. Los compuestos aislados de T. patula se utilizaron para examinar la actividad citotóxica y la producción total de especies reactivas de oxígeno en las células SiHa y HeLa; las células también se caracterizaron mediante microscopía electrónica de barrido. Patulitrina resultó citotóxica para las células SiHa y HeLa. Se observó un aumento en la producción de ROS en diferentes momentos del tratamiento de las células con patuletina y patulit rina. La microscopía electrónica de barrido mostró cambios morfológicos en las células SiHa y HeLa. Por lo tanto, los compuestos aislados de T. patula tienen un gran potencial de tratamiento contra el cáncer cervical.
Assuntos
Humanos , Flavonoides/isolamento & purificação , Extratos Vegetais/química , Neoplasias do Colo do Útero/tratamento farmacológico , Anticarcinógenos/química , Tagetes/química , Extratos Vegetais/administração & dosagem , Microscopia Eletrônica de Varredura , Cromatografia Líquida de Alta Pressão , Anticarcinógenos/administração & dosagem , Linhagem Celular Tumoral/efeitos dos fármacosRESUMO
INTRODUCCIÓN: Cuadro clínico: En el Perú, para el 2020, se estimaron 4,270 casos nuevos y 2,288 muertes por cáncer de cérvix. La tasa de incidencia fue de 15.2 casos nuevos por cada 100,000 mujeres y la tasa de mortalidad fue de 11.5 muertes por cada 100,000 mujeres. En consecuencia, el cáncer de cérvix ocupa el segundo lugar entre los cánceres más frecuentes y el segundo lugar entre las causas de muerte por cáncer más frecuente entre mujeres en el Perú. La supervivencia global (SG) a 5 años es, aproximadamente, 92%, 65% y 17% para la enfermedad en etapa temprana, localmente avanzada y metastásica, respectivamente. El pronóstico de las mujeres con enfermedad recurrente es desfavorable, excepto en los casos de recurrencia local en quienes se puede brindar tratamiento curativo. En etapas avanzadas, la quimioterapia es la piedra angular del tratamiento. Sin embargo, la tasa de respuesta suele ser de 13% con el uso de quimioterapia en base a solo cisplatino, y de 36% con el uso de la quimioterapia en base a cisplatino combinado con paclitaxel o similares. En base a lo anterior, se están evaluando nuevas alternativas terapéuticas que puedan ser añadidas al esquema quimioterápico para mejorar la supervivencia de mujeres con esta neoplasia. Entre estas alternativas terapéuticas, se ha propuesto el uso de agentes inmunoterapéuticos que actúen a nivel de la proteína de puntos de control (PD 1) como pembrolizumab. Tecnología sa
Assuntos
Humanos , Imunoglobulina G/uso terapêutico , Neoplasias do Colo do Útero/tratamento farmacológico , Cisplatino/uso terapêutico , Inibidores de Checkpoint Imunológico , Metástase Neoplásica/tratamento farmacológico , Avaliação em Saúde/economia , Eficácia , Análise Custo-Benefício/economiaRESUMO
INTRODUCTION: Despite the evidence that photodynamic therapy (PDT) associated with chemotherapy presents great potential to overcome the limitations of monotherapy, little is known about the current status of this combination against cervical cancer. This systematic review aimed to address the currently available advances in combining PDT and chemotherapy in different research models and clinical trials of cervical cancer. METHODS: We conducted a systematic review based on PRISMA Statement and Open Science Framework review protocol using PubMed, Web of Science, Embase, Scopus, LILACS, and Cochrane databases. We selected original articles focusing on 'Uterine Cervical Neoplasms' and 'Photochemotherapy and Chemotherapy' published in the last 10 years. The risk of bias in the studies was assessed using the CONSORT and SYRCLE tools. RESULTS: Twenty-three original articles were included, focusing on HeLa cells, derived from endocervical adenocarcinoma and on combinations of several chemotherapeutics. Most of the combinations used modern drug delivery systems for improved simultaneous delivery and presented promising results with increased cytotoxicity compared to monotherapy. CONCLUSION: Despite the scarcity of animal studies and the absence of clinical studies, the combination of chemotherapy with PDT presents a potential option for cervical cancer therapy requiring additional studies. OSF REGISTRATION: https://doi.org/10.17605/OSF.IO/WPHN5 [Figure: see text].
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Fotoquimioterapia , Neoplasias do Colo do Útero , Humanos , Fotoquimioterapia/métodos , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/patologia , Feminino , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Terapia Combinada , Células HeLa , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Sistemas de Liberação de Medicamentos , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Fármacos Fotossensibilizantes/administração & dosagem , Fármacos Fotossensibilizantes/farmacologiaRESUMO
Cervical cancer is a specific type of cancer that affects women around the world, with an incidence of 604â thousand new cases per year and 341â thousand deaths. There is a high demand for new effective antineoplastic drugs with few side effects. In this sense, recent research highlights the potential of compounds of natural origin in treating and preventing different types of cancer. Myrciaria glazioviana is a Brazilian native species belonging to the Myrtaceae family, which has previously described biological activities such as antimicrobial, anti-inflammatory, and antioxidant properties. This study aims to evaluate the anticancer activity of the dichloromethane extract (MGD) and ethyl acetate extract (MGA) of M. glazioviana leaves against human cervical cancer cell line (HeLa), as well as to identify their bioactive compounds. Using HPLC-HRESIMS technique, ten compounds were characterized in both samples: quinic acid, ellagic acid, Tri-O-methyl ellagic acid, two derivatives of Tetra-O-methyl flavellagic acid, quercetrin, Di-O-methyl ellagic acid, and three derivatives of pentamethyl coruleoellagic acid. Through MTT assays using HeLa cells and NIH/3T3 cells, it was observed that MGD and MGA were selective against tumor cells, with IC50 values of 24.31 and 12.62â µg/mL, respectively. The samples induced the tumor cell death by apoptosis, as evidenced by the activation of caspases 3/7, cell shrinkage, and pyknotic nuclei. Both samples were also able to inhibit the migration of HeLa cells after 24â hours of treatment, indicating a potential antimetastatic effect. Therefore, the present research highlights the antiproliferative and antimigratory potential of this species against HeLa cells.
Assuntos
Antineoplásicos Fitogênicos , Apoptose , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Myrtaceae , Extratos Vegetais , Neoplasias do Colo do Útero , Humanos , Células HeLa , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Proliferação de Células/efeitos dos fármacos , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/patologia , Myrtaceae/química , Cromatografia Líquida de Alta Pressão , Apoptose/efeitos dos fármacos , Feminino , Relação Dose-Resposta a Droga , Camundongos , Folhas de Planta/química , Animais , Sobrevivência Celular/efeitos dos fármacos , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Cervical cancer is one of the most common malignancies in women that continues to be a public health problem worldwide. Human papillomavirus (HPV) infection is closely related as the causative agent of almost all cases of cervical cancer. Currently, there is no effective treatment for the persistence of HPV. Although vaccines have shown promising results in recent years, they are still a costly strategy for developing countries and have no therapeutic effect on existing infections, which is why the need arises to search for new strategies that can be used in treatment, suppressing oncogenic HPV and disease progression. Extracts of Schisandra Chinensis and Pueraria lobata have been used in traditional medicine, and it has been shown in recent years that some of their bioactive compounds have pharmacological, antioxidant, antitumor, apoptotic, and proliferation effects in HPV-positive cells. However, its mechanism of action has yet to be fully explored. AIM OF THE STUDY: The following study aimed to determine the chemical composition, antioxidant activity, and potential antiproliferative and viral oncogene effects of natural extracts of S. chinensis and P. lobata on HPV-18 positive cervical cancer cells. MATERIALS AND METHODS: The HPV-18-positive HeLa cells were treated for 24 and 48 h with the ethanolic extracts of S chinensis and P. lobata. Subsequently, cell viability was evaluated using the resazurin method, the effect on the cell cycle of the extracts (1.0, 10, and 100 µg/mL) was measured by flow cytometry, the gene of expression of the E6/E7, P53, BCL-2, and E2F-1 were determined by RT-PCR and the protein expression of p53, Ki-67, x|and Bcl-2 by immunohistochemistry. Additionally, the chemical characterization of the two extracts was carried out using LC-MS, and the total phenolics content (TPC), Total flavonoid content (TFC), and DPPH radical scavenging capacity were determined. Data were analyzed using the Mann-Whitney and Kruskal Wallis U test with GraphPad Prism 6 software. RESULTS: The natural extracts of Schisandra chinensis and Pueraria lobata induced down-regulation of E6 HPV oncogene (p<0.05) and a strong up-regulation of P53 (p<0.05), E2F-1 (p<0.05), and Bcl-2 (p<0.05) gene expression. Simultaneously, the natural extracts tend to increase the p53 protein levels and arrest the cell cycle of HeLa in the G1/S phase (p<0.05). Investigated extracts were characterized by the occurrence of bioactive lignans and isoflavones in S. chinensis and P. lobata, respectively. CONCLUSION: The extracts of S. chinensis and P. lobata within their chemical characterization mainly present lignan and isoflavone-type compounds, which are probably responsible for inhibiting the expression of the HPV E6 oncogene and inducing an increase in the expression of p53, Bcl -2 and E2F-1 producing cell cycle detection in S phase in HeLa cells. Therefore, these extracts are good candidates to continue studying their antiviral and antiproliferative potential in cells transformed by HPV.
Assuntos
Infecções por Papillomavirus , Pueraria , Schisandra , Neoplasias do Colo do Útero , Humanos , Feminino , Células HeLa , Papillomavirus Humano , Proteína Supressora de Tumor p53/genética , Neoplasias do Colo do Útero/tratamento farmacológico , Regulação para Baixo , Infecções por Papillomavirus/tratamento farmacológico , Oncogenes , Proteínas Proto-Oncogênicas c-bcl-2 , AntioxidantesRESUMO
Despite advances in chemotherapeutic drugs used against cervical cancer, available chemotherapy treatments adversely affect the patient's quality of life. For this reason, new molecules from natural sources with antitumor potential and few side effects are required. In previous research, Pllans-II, a phospholipase A2 type-Asp49 from Porthidium lansbergii lansbergii snake venom, has shown selective attack against the HeLa and Ca Ski cervical cancer cell lines. This work suggests that the cytotoxic effect generated by Pllans-II on HeLa cells is triggered without affecting the integrity of the cytoplasmic membrane or depolarizing the mitochondrial membranes. The results allow us to establish that cell death in HeLa is related to the junction blockage between α5ß1 integrins and fibronectin of the extracellular matrix. Pllans-II reduces the cells' ability of adhesion and affects survival and proliferation pathways mediated by intracellular communication with the external environment. Our findings confirmed Pllans-II as a potential prototype for developing a selective chemotherapeutic drug against cervical cancer.
Assuntos
Antineoplásicos , Neoplasias do Colo do Útero , Feminino , Humanos , Neoplasias do Colo do Útero/tratamento farmacológico , Adesão Celular , Células HeLa , Qualidade de Vida , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Integrina alfa5beta1RESUMO
The antitumor potential of proteins from snake venoms has been studied in recent decades, and evidence has emerged that phospholipases A2 can selectively attack cells of various types of tumors. Previous results have shown that phospholipase A2 "Pllans-II," isolated from Porthidium lansbergii lansbergii snake venom, displayed antitumoral activity on cervical cancer and did not alter the viability of non-tumorigenic cells. However, until now, there was no evidence of its safety at the local and systemic levels, nor had experiments been developed to demonstrate that its production using recombinant technology allows us to obtain a molecule with effects similar to those generated by native phospholipase. Thus, we evaluated the impact caused by Pllans-II on murine biomodels, determining whether it induced local hemorrhage or increased pro-inflammatory and liver damage markers and histological alterations in the liver and kidneys. Additionally, the protein was produced using recombinant technology using a pET28a expression vector and the BL21 (DE3) Escherichia coli strain. Equally, its enzymatic activity and anticancer effect were evaluated on cervical cancer lines such as HeLa and Ca Ski. The results demonstrated that Pllans-II did not generate hemorrhagic activity, nor did it increase the pro-inflammatory cytokines IL-6, IL-1B, or TNF-α at doses of 3.28, 1.64, and 0.82 mg/kg. There was also no evidence of organ damage, and only ALT and AST increased in mild levels at the two highest concentrations. Additionally, the recombinant version of Pllans-II showed conservation in its catalytic activity and the ability to generate death in HeLa and Ca Ski cells (42% and 23%, respectively). These results demonstrate the innocuity of Pllans-II at the lowest dose and constitute an advance in considering a molecule produced using recombinant technology a drug candidate for selective attacks against cervical cancer.