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Métodos Terapêuticos e Terapias MTCI
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1.
J Exp Clin Cancer Res ; 40(1): 114, 2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33785035

RESUMO

BACKGROUND: Colorectal cancer (CRC) is a clinically challenging malignant tumor worldwide. As a natural product and sesquiterpene lactone, Costunolide (CTD) has been reported to possess anticancer activities. However, the regulation mechanism and precise target of this substance remain undiscovered in CRC. In this study, we found that CTD inhibited CRC cell proliferation in vitro and in vivo by targeting AKT. METHODS: Effects of CTD on colon cancer cell growth in vitro were evaluated in cell proliferation assays, migration and invasion, propidium iodide, and annexin V-staining analyses. Targets of CTD were identified utilizing phosphoprotein-specific antibody array; Costunolide-sepharose conjugated bead pull-down analysis and knockdown techniques. We investigated the underlying mechanisms of CTD by ubiquitination, immunofluorescence staining, and western blot assays. Cell-derived tumour xenografts (CDX) in nude mice and immunohistochemistry were used to assess anti-tumour effects of CTD in vivo. RESULTS: CTD suppressed the proliferation, anchorage-independent colony growth and epithelial-mesenchymal transformation (EMT) of CRC cells including HCT-15, HCT-116 and DLD1. Besides, the CTD also triggered cell apoptosis and cell cycle arrest at the G2/M phase. The CTD activates and induces p53 stability by inhibiting MDM2 ubiquitination via the suppression of AKT's phosphorylation in vitro. The CTD suppresses cell growth in a p53-independent fashion manner; p53 activation may contribute to the anticancer activity of CTD via target AKT. Finally, the CTD decreased the volume of CDX tumors without of the body weight loss and reduced the expression of AKT-MDM2-p53 signaling pathway in xenograft tumors. CONCLUSIONS: Our project has uncovered the mechanism underlying the biological activity of CTD in colon cancer and confirmed the AKT is a directly target of CTD. All of which These results revealed that CTD might be a new AKT inhibitor in colon cancer treatment, and CTD is worthy of further exploration in preclinical and clinical trials.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sesquiterpenos/uso terapêutico , Animais , Apoptose , Feminino , Humanos , Camundongos , Sesquiterpenos/farmacologia , Transfecção , Ensaios Antitumorais Modelo de Xenoenxerto
2.
BMC Complement Altern Med ; 19(1): 347, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31791315

RESUMO

BACKGROUND: The root bark of Dictamnus dasycarpus Turcz. has been successfully used for the treatment of inflammatory skin conditions such as eczema and pruritus. However, the anti-psoriatic effect of this plant has not until now been investigated. METHODS: The aim of this project was to investigate whether a methanol extract of Dictamnus dasycarpus Turcz. root bark (MEDD) can be used as a therapeutic agent for psoriasis in C57BL/6 mice model of imiquimod (IMQ)-induced psoriasis. IMQ and MEDD was applied to mouse skin continuously for 7 days. The skin phenotype and the levels of inflammatory cytokines, such as interferon (IFN)-γ and interleukin (IL)-17, were analyzed. The immune cell population was determined by flow cytometry, and STAT1 and 3 protein levels were measured. RESULTS: An alleviation of scaly skin phenotype, immune cell infiltration in the dermis, and epidermal hyperplasia was observed after daily MEDD treatment in the lesion-affected area. It was also found that MEDD reduced IL-17 cytokine levels decreased by 44.37% (p < 0.05), the number of IL-17-producing Th17 cells and γδT cells, and the size of the Th1 population secreting IFN-γ decreased by 45.98, 62.21, and 44.42%, respectively (p < 0.05), compared with the vehicle control group. STAT3 signals, associated with IL-17 are also reduced by MEDD. CONCLUSIONS: An anti-psoriatic effect of MEDD was observed, as determined by decreased skin inflammation, reduced number of inflammatory cytokines, and a smaller population of inflammatory cells. These results contribute to the validation of the use of MEDD in the treatment of psoriasis.


Assuntos
Anti-Inflamatórios/farmacologia , Dictamnus , Imiquimode/efeitos adversos , Extratos Vegetais/farmacologia , Psoríase , Animais , Citocinas/metabolismo , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Casca de Planta/química , Psoríase/induzido quimicamente , Psoríase/metabolismo , Fator de Transcrição STAT3/metabolismo , Pele/efeitos dos fármacos , Pele/patologia , Linfócitos T Auxiliares-Indutores
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