Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 3 de 3
Mais filtros

Base de dados
Intervalo de ano de publicação
Cancer Lett ; 515: 36-48, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34052328


Upregulated expression of immune checkpoint molecules correlates with exhausted phenotype and impaired function of cytotoxic T cells to evade host immunity. By disrupting the interaction of PD-L1 and PD1, immune checkpoint inhibitors can restore immune system function against cancer cells. Growing evidence have demonstrated apigenin and luteolin, which are flavonoids abundant in common fruits and vegetables, can suppress growth and induce apoptosis of multiple types of cancer cells with their potent anti-inflammatory, antioxidant and anticancer properties. In this study, the effects and underlying mechanisms of luteolin, apigenin, and anti-PD-1 antibody combined with luteolin or apigenin on the PD-L1 expression and anti-tumorigenesis in KRAS-mutant lung cancer were investigated. Luteolin and apigenin significantly inhibited lung cancer cell growth, induced cell apoptosis, and down-regulated the IFN-γ-induced PD-L1 expression by suppressing the phosphorylation of STAT3. Both luteolin and apigenin showed potent anti-cancer activities in the H358 xenograft and Lewis lung carcinoma model in vivo, and the treatment with monoclonal PD1 antibody enhanced the infiltration of T cells into tumor tissues. Apigenin exhibited anti-tumor activity in Genetically engineered KRASLA2 mice. In conclusion, both apigenin and luteolin significantly suppressed lung cancer with KRAS mutant proliferation, and down-regulated the IFN-γ induced PD-L1 expression. Treatment with the combination of PD-1 blockade and apigenin/luteolin has a synergistic effect and might be a prospective therapeutic strategy for NSCLC with KRAS-mutant.

Apigenina/farmacologia , Antígeno B7-H1/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Luteolina/farmacologia , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Células A549 , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Feminino , Humanos , Interferon gama/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus
Pharmacol Res ; 169: 105656, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33964470


Non-small cell lung cancer (NSCLC) is one of the most frequently diagnosed cancers and the leading causes of cancer death worldwide. Therefore, new therapeutic agents are urgently needed to improve patient outcomes. Plumbagin (PLB), a natural sesquiterpene present in many Chinese herbal medicines, has been reported for its anti-cancer activity in various cancer cells. In this study, the effects and underlying mechanisms of PLB on the tumorigenesis of NSCLC were investigated. PLB dose-dependently inhibited the growth of NSCLC cell lines. PLB promoted ROS production, activated the endoplasmic reticulum (ER) stress pathway, and induced cell apoptosis, accompanied by the decreased expression level of ADP-ribosylation factor 1 (ARF1) in NSCLC cancer cells, and those effects of PLB could be reversed by the pretreatment with N-acetyl-L-cysteine (NAC). More importantly, the calcium chelator (BM) significantly reversed PLB-induced cell apoptosis. Furthermore, PLB significantly inhibited the growth of both H1975 xenograft and LLC1 tumors and exhibited antitumor activity by enhancing the number and the effector function of CD8+ T cells in KRASLA2 mice model and the LLC1 xenograft. Our findings suggest that PLB exerts potent antitumor activity against NSCLC in vitro and in vivo through ARF1 downregulation and induction of antitumor immune response, indicating that PLB is a new novel therapeutic candidate for the treatment of patients with NSCLC.

Fator 1 de Ribosilação do ADP/metabolismo , Antineoplásicos Fitogênicos/uso terapêutico , Linfócitos T CD8-Positivos/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Naftoquinonas/uso terapêutico , Animais , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Feminino , Ativação Linfocitária/efeitos dos fármacos , Camundongos Nus , Naftoquinonas/farmacologia , Transplante de Neoplasias
Chin Med Sci J ; 32(3): 135-144, 2017 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-28956740


Objective To genetically correct a disease-causing point mutation in human induced pluripotent stem cells (iPSCs) derived from a hemophilia B patient. Methods First, the disease-causing mutation was detected by sequencing the encoding area of human coagulation factor IX (F IX) gene. Genomic DNA was extracted from the iPSCs, and the primers were designed to amplify the eight exons of F IX. Next, the point mutation in those iPSCs was genetically corrected using CRISPR/Cas9 technology in the presence of a 129-nucleotide homologous repair template that contained two synonymous mutations. Then, top 8 potential off-target sites were subsequently analyzed using Sanger sequencing. Finally, the corrected clones were differentiated into hepatocyte-like cells, and the secretion of F IX was validated by immunocytochemistry and ELISA assay. Results The cell line bore a missense mutation in the 6th coding exon (c.676 C>T) of F IX gene. Correction of the point mutation was achieved via CRISPR/Cas9 technology in situ with a high efficacy at about 22% (10/45) and no off-target effects detected in the corrected iPSC clones. F IX secretion, which was further visualized by immunocytochemistry and quantified by ELISA in vitro, reached about 6 ng/ml on day 21 of differentiation procedure. Conclusions Mutations in human disease-specific iPSCs could be precisely corrected by CRISPR/Cas9 technology, and corrected cells still maintained hepatic differentiation capability. Our findings might throw a light on iPSC-based personalized therapies in the clinical application, especially for hemophilia B.

Diferenciação Celular , Fator IX , Terapia Genética , Hemofilia B , Células-Tronco Pluripotentes Induzidas/metabolismo , Mutação , Fator IX/genética , Fator IX/metabolismo , Hemofilia B/genética , Hemofilia B/metabolismo , Hemofilia B/patologia , Hemofilia B/terapia , Humanos , Células-Tronco Pluripotentes Induzidas/patologia