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1.
Toxicology ; 435: 152422, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32112805

RESUMO

Ribavirin has been proven to be an antiviral treatment, whereas there are still risks of hemolysis and congenital malformation. Abnormal cardiac development contributes to the occurrence and development of many heart diseases. However, there is so far no evidence that ribavirin induces human cardiac developmental toxicity. Herein, we employed the cardiac differentiation model of human induced pluripotent stem cells (hiPSCs) to determine the impact of ribavirin on heart development. Our data showed that ribavirin at clinically high concentrations (5 and 10 µM) significantly inhibited the proliferation and differentiation of hiPSCs from mesoderm to cardiac progenitor cells and cardiac progenitor cells to cardiomyocytes, but not from pluripotent status to mesoderm. Meanwhile, DCFH-DA staining revealed that ribavirin could increase ROS content in the mid-phase of differentiation. In addition, ribavirin treatment (1, 5 and 10 µM) remarkably caused DNA damage which was shown by the increase of γH2AX-positive cells and upregulation of the p53 during the differentiation of hiPSCs from mesoderm to cardiac progenitor cells. Moreover, exposuring to ribavirin (5 and 10 µM) markedly upregulated the expression of lncRNAs Gas5 in both mid-phase and late phase of differentiation and HBL1 in the mid-phase. In conclusion, our results suggest that ribavirin is detrimental in cardiac differentiation of hiPSCs, which may be associated with DNA damage, upregulated p53 and increased Gas5. It may provide the evidence for the rational clinical application of ribavirin.

2.
FEBS Open Bio ; 2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32053740

RESUMO

Iron overload affects the cell cycle of various cell types, but the effect of iron overload on human pluripotent stem cells (hPSCs) has not yet been reported. Here, we show that the proliferation capacities of human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) were significantly inhibited by ferric ammonium citrate (FAC) in a concentration-dependent manner. Additionally, deferoxamine (DFO) protected hESCs/hiPSCs against FAC-induced cell cycle arrest. However, iron overload did not affect pluripotency in hESCs/hiPSCs. Further, treatment of hiPSCs with FAC resulted in excess reactive oxygen species production and DNA damage. Collectively, our findings provide new insights into the role of iron homeostasis in the maintenance of self-renewal in hPSCs.

3.
J Cell Physiol ; 235(3): 2753-2760, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31541452

RESUMO

Cardiomyocytes differentiated from human-induced pluripotent stem cells (hiPSCs) hold great potential for therapy of heart diseases. However, the underlying mechanisms of its cardiac differentiation have not been fully elucidated. Hippo-YAP signal pathway plays important roles in cell differentiation, tissue homeostasis, and organ size. Here, we identify the role of Hippo-YAP signal pathway in determining cardiac differentiation fate of hiPSCs. We found that cardiac differentiation of hiPSCs were significantly inhibited after treatment with verteporfin (a selective and potent YAP inhibitor). During hiPSCs differentiation from mesoderm cells (MESs) into cardiomyocytes, verteporfin treatment caused the cells retained in the earlier cardiovascular progenitor cells (CVPCs) stage. Interestingly, during hiPSCs differentiation from CVPC into cardiomyocytes, verteporfin treatment induced cells dedifferentiation into the earlier CVPC stage. Mechanistically, we found that YAP interacted with transcriptional enhanced associate domain transcription factor 3 (TEAD3) to regulate cardiac differentiation of hiPSCs during the CVPC stage. Consistently, RNAi-based silencing of TEAD3 mimicked the phenotype as the cells treated with verteporfin. Collectively, our study suggests that YAP-TEAD3 signaling is important for cardiomyocyte differentiation of hiPSCs. Our findings provide new insight into the function of Hippo-YAP signal in cardiovascular lineage commitment.

4.
J Exp Clin Cancer Res ; 38(1): 385, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31481102

RESUMO

In the original publication of this article [1], there are mistakes in Fig. 3A and Fig. 3D.

5.
Artigo em Inglês | MEDLINE | ID: mdl-31186662

RESUMO

In oriental medicine, mixtures of medical plants are always used as prescriptions for diseases. Natural products extracted from herbs have great potential antiaging effects. Previous studies and clinical trials have shown several critical functions of Erjingwan (EJW), such as nourishing Yin, kidney tonifying and aging-resistance. We assumed that EJW extracts exerted the antiaging effects through nourishing Yin. We examined the antiaging effects of EJW extracts on healthy human skin by noninvasive measurements. Then we estimated the cell proliferation and DPPH radical scavenging rate. Western blotting analysis was used to determine the expressions of matrix metalloproteinase-1 (MMP-1), type I collagen (COL1A2), p-NF-κB, NF-κB, p-IκBα, IκBα, p-Nrf2, and HO-1. EJW extracts did not affect moisture content, TEWL and skin chroma, while it significantly improved skin glossiness and skin elasticity. Moreover, EJW extracts could downregulate the MMP1 expression and upregulate the COL1A2 expression. In addition, it promoted the Nrf2 pathway while it inhibited the NF-κB pathway. With the application of cream containing EJW extracts, the skin aging state was significantly improved. Furthermore, in vitro studies showed that EJW extracts contributed to the repair of skin after injury. Taken together, the antiaging effects of EJW extracts were related to its antioxidant and anti-inflammatory abilities.

6.
Toxicol Lett ; 309: 51-58, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30946857

RESUMO

Arsenic trioxide (ATO) has been recommended as the first-line agent for the treatment of acute promyelocytic leukaemia (APL), due to its substantial anticancer effect. Numerous clinical reports have indicated that ATO is a developmental toxicant which can result in birth defects of human beings. But whether arsenic trioxide can lead to human cardiac developmental toxicity remains largely unknown. So the present study aims to explore the influence and mechanisms of ATO on human cardiac development by using a vitro cardiac differentiation model of human induced pluripotent stem cells (hiPSCs). Here we found that clinically achievable concentrations (0.1, 0.5 and 1 µM) of ATO resulted in a significant inhibition of proliferation during the whole process of cardiac differentiation of hiPSCs. Meanwhile, TUNEL assay revealed that ATO could cause cell apoptosis during cardiac differentiation in a concentration-dependent manner. Consistently, we found that ATO reduced the expressions of mesoderm markers Brachyury and EOMES, cardiac progenitor cell markers GATA-4, MESP-1 and TBX-5, and cardiac specific marker α-actinin in differentiated hiPSCs. Furthermore, ATO treatment had caused DNA damage which was shown in the upregulation of γH2AX, a sensitive marker for DNA double-strand breaks. Taken together, ATO blocked cardiomyocyte differentiation, induced apoptosis and cell growth arrest during cardiac differentiation of hiPSCs, which might be associated with DNA damage.


Assuntos
Trióxido de Arsênio/toxicidade , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Dano ao DNA , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/fisiologia , Mesoderma/citologia , Mesoderma/efeitos dos fármacos , Miócitos Cardíacos/citologia
7.
Int J Biol Sci ; 15(2): 386-394, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30745828

RESUMO

Arsenic trioxide (ATO) has been well recognized as an anti-tumor agent for various human cancers. Recently, the blue light emitting diodes (LEDs)-based therapy has also been demonstrated to be potential therapeutic strategies for several cancers. However, the combination effects of ATO and blue LED on tumor suppression are still unclear. In this study, we determined whether combination of ATO and blue LED irradiation at 470 nm in wavelength exhibited superior anti-tumor activity in human osteosarcoma (OS). We observed that combination treatments of ATO and blue LED much more significantly decreased the percentages of proliferative cells, and increased apoptotic rate compared with any single treatments in U-2 OS cells. Furthermore, we found suppression of cell migration and invasion were much more pronounced in ATO plus blue LED treated group than single treated groups. Moreover, reactive oxygen species (ROS) assay and immunostaining of γ-H2A.X and p53 indicated that the combined treatments resulted in further markedly increases in ROS accumulation, DNA damage and p53 activity. Taken together, our study demonstrated synergistical anti-tumor effects of combined treatments of ATO and blue LED on human OS cells, which were associated with an increased ROS accumulation, DNA damaged mediated p53 activation.


Assuntos
Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Trióxido de Arsênio/farmacologia , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/efeitos da radiação , Osteossarcoma/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Western Blotting , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Humanos , Marcação In Situ das Extremidades Cortadas , Espécies Reativas de Oxigênio/metabolismo , Proteína Supressora de Tumor p53/genética
8.
J Ethnopharmacol ; 234: 180-188, 2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-30660711

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Ze-Qi-Tang (ZQT), a classic Chinese herbal formula, has been for over thousand years used for the treatment of several respiratory ailments like cough, asthma, hydrothorax and lung cancer. AIM OF STUDY: Cumulative literature on ZQT herbal formula reveals that its several constituent components are potent inducer of apoptosis in different cancer cells. However, the activity of ZQT against non-small-cell-lung cancer (NSCLC) has not been previously examined. The aim of the study is to investigate the molecular mechanism of ZQT on NSCLC cells. MATERIALS AND METHODS: Cell growth were determined by CCK-8 and colony formation assay. Induction of cellular apoptosis or arrest of cell cycle were determined by flow cytometric analysis using annexin V/ propidium iodide, Hoechst 33342 or TUNEL staining method. In some assay p53 activity of NSCLC ( A549 and H460) cells were blocked with pifithrin-a, prior to treatment with ZQT. The level of expression of cell cycle and apoptosis related marker proteins were estimated by western blot. The anticancer activity of ZQT in vivo were monitored in nude mice that were induced with tumor by subcutaneous inoculation of A549 cells and then treated by ZQT(100 mg/kg,200 mg/kg,400 mg/kg) gavaging for 30 days. Mice' body weight and tumor volume were measured weekly. The survival carve was recorded. Apoptosis from mice' tissue was observed by TUNEL assay. Pathological histology of liver, kidney and heart were detected by H&E staining, and its functions were tested by ELISA. RESULTS: Dose- and time-dependent inhibition of proliferation of NSCLC ( A549 and H460) cells by ZQT therapy along with induction of cell cycle arrest at G0/G1 phase were observed. The arrest of cell cycle arrest and inhibition of cellular proliferation were associated with up regulation of p53 along with down regulation of Cyclin B1 and Cdk2 indicating a mitochondrial related induction of apoptosis with ZQT. A reversal of ZQT-induced apoptosis and G0/G1 arrest was observed with pifithrin-a pretreatment. ZQT was also found to suppress the progression of tumor growth in mouse xenograft models and prolong survival. In addition, no hepato- or nephro- or cardio-toxicity with ZQT treatment were detected in mice. CONCLUSION: These findings suggest that the ZQT formula inhibits the growth of NSCLC cells and is a potential agent of complementary and alternative treatment for lung cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Células A549 , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/toxicidade , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/patologia , Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/toxicidade , Humanos , Neoplasias Pulmonares/patologia , Masculino , Medicina Tradicional Chinesa/métodos , Camundongos , Camundongos Nus , Fatores de Tempo , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Stem Cells ; 37(4): 489-503, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30599084

RESUMO

Iron homeostasis is crucial for a variety of biological processes, but the biological role of iron homeostasis in pluripotent stem cells (PSCs) remains largely unknown. The present study aimed to determine whether iron homeostasis is involved in maintaining the pluripotency of human PSCs (hPSCs). We found that the intracellular depletion of iron leads to a rapid downregulation of NANOG and a dramatic decrease in the self-renewal of hPSCs as well as spontaneous and nonspecific differentiation. Moreover, long-term depletion of iron can result in the remarkable cell death of hPSCs via apoptosis and necrosis pathways. Additionally, we found that the depletion of iron increased the activity of lipoprotein-associated phospholipase A2 (LP-PLA2) and the production of lysophosphatidylcholine, thereby suppressing NANOG expression by enhancer of zeste homolog 2-mediated trimethylation of histone H3 lysine 27. Consistently, LP-PLA2 inhibition abrogated iron depletion-induced loss of pluripotency and differentiation. Altogether, the findings of our study demonstrates that iron homeostasis, acting through glycerophospholipid metabolic pathway, is essential for the pluripotency and survival of hPSCs. Stem Cells 2019;37:489-503.

10.
Curr Drug Targets ; 20(7): 763-774, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30539693

RESUMO

Owning the high incidence and disability rate in the past decades, to be expected, cardiovascular diseases (CVDs) have become one of the leading death causes worldwide. Currently, induced pluripotent stem cells (iPSCs), with the potential to form fresh myocardium and improve the functions of damaged hearts, have been studied widely in experimental CVD therapy. Moreover, iPSC-derived cardiomyocytes (CMs), as novel disease models, play a significant role in drug screening, drug safety assessment, along with the exploration of pathological mechanisms of diseases. Furthermore, a lot of studies have been carried out to clarify the biological basis of iPSCs and its derived cells in the treatment of CVDs. Their molecular mechanisms were associated with release of paracrine factors, regulation of miRNAs, mechanical support of new tissues, activation of specific pathways and specific enzymes, etc. In addition, a few small chemical molecules and suitable biological scaffolds play positive roles in enhancing the efficiency of iPSC transplantation. This article reviews the development and limitations of iPSCs in CVD therapy, and summarizes the latest research achievements regarding the application of iPSCs in CVDs.

11.
Mol Ther Nucleic Acids ; 19: 421-436, 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31896070

RESUMO

Methyltransferase-like 3 (METTL3) is the main enzyme for N6-methyladenosine (m6A)-based methylation of RNAs and it has been implicated in many biological and pathophysiological processes. In this study, we aimed to explore the potential involvement of METTL3 in osteoblast differentiation and decipher the underlying cellular and molecular mechanisms. We demonstrated that METTL3 is downregulated in human osteoporosis and the ovariectomized (OVX) mouse model, as well as during the osteogenic differentiation. Silence of METTL3 by short interfering RNA (siRNA) decreased m6A methylation levels and inhibited osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) and reduced bone mass, and similar effects were observed in METTL3+/- knockout mice. In contrast, adenovirus-mediated overexpression of METTL3 produced the opposite effects. In addition, METTL3 enhanced, whereas METTL3 silence or knockout suppressed, the m6A methylations of runt-related transcription factor 2 (RUNX2; a key transcription factor for osteoblast differentiation and bone formation) and precursor (pre-)miR-320. Moreover, downregulation of mature miR-320 rescued the decreased bone mass caused by METTL3 silence or METTL3+/- knockout. Therefore, METTL3-based m6A modification favors osteogenic differentiation of BMSCs through m6A-based direct and indirect regulation of RUNX2, and abnormal downregulation of METTL3 is likely one of the mechanisms underlying osteoporosis in patients and mice. Thus, METTL3 overexpression might be considered a new approach of replacement therapy for the treatment of human osteoporosis.

12.
Autophagy ; 14(10): 1831-1844, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29969944

RESUMO

Targeting macroautophagy/autophagy is a novel strategy in cancer immunotherapy. In the present study, we showed that the natural product rocaglamide (RocA) enhanced natural killer (NK) cell-mediated lysis of non-small cell lung cancer (NSCLC) cells in vitro and tumor regression in vivo. Moreover, this effect was not related to the NK cell recognition of target cells or expressions of death receptors. Instead, RocA inhibited autophagy and restored the level of NK cell-derived GZMB (granzyme B) in NSCLC cells, therefore increasing their susceptibility to NK cell-mediated killing. In addition, we further identified that the target of RocA was ULK1 (unc-51 like autophagy activating kinase 1) that is required for autophagy initiation. Using firefly luciferase containing the 5´ untranslated region of ULK1, we found that RocA inhibited the protein translation of ULK1 in a sequence-specific manner. Taken together, RocA could block autophagic immune resistance to NK cell-mediated killing, and our data suggested that RocA was a promising therapeutic candidate in NK cell-based cancer immunotherapy.


Assuntos
Autofagia , Benzofuranos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Células Matadoras Naturais/imunologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Animais , Autofagia/efeitos dos fármacos , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Degranulação Celular/efeitos dos fármacos , Granzimas/metabolismo , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos SCID , Modelos Biológicos , Biossíntese de Proteínas , Receptores de Morte Celular/metabolismo
13.
Br J Cancer ; 117(11): 1621-1630, 2017 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-29024939

RESUMO

BACKGROUND: The identification of bioactive compounds from Chinese medicine plays a crucial role in the development of novel reagents against non-small lung cancer (NSCLC). METHODS: High throughput screening assay and analyses of cell growth, cell cycle, apoptosis, cDNA microarray, BrdU incorporation and gene expression were performed. RESULTS: Ailanthone (Aila) suppressed NSCLC cell growth and colony formation in vitro and inhibited NSCLC tumour growth in subcutaneously xenografted and orthotopic lung tumour models, leading to prolonged survival of tumour-bearing mice. Moreover, Aila induced cell cycle arrest in a dose-independent manner but did not induce apoptosis in all NSCLC cells. Furthermore, 1222 genes were differentially expressed upon Aila administration, which were involved in 21 signal pathways, such as DNA replication. In addition, Aila dose-dependently decreased BrdU incorporation and downregulated the expression of replication protein A1 (RPA1). CONCLUSIONS: Aila inhibited the growth of NSCLC cells through the repression of DNA replication via downregulating RPA1, rather than through cell cycle arrest and apoptosis. Our findings suggested that Aila could be used as a promising therapeutic candidate for NSCLC patients.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Replicação do DNA/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Quassinas/farmacologia , Proteína de Replicação A/genética , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Regulação para Baixo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto
14.
J Exp Clin Cancer Res ; 36(1): 124, 2017 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-28893319

RESUMO

BACKGROUND: Pancreatic cancer is generally acknowledged as the most common primary malignant tumor, and it is known to be resistant to conventional chemotherapy. Novel, selective antitumor agents are pressingly needed. METHODS: CCK-8 and colony formation assay were used to investigate the cell growth. Flow cytometry analysis was used to evaluate the cell cycle and cell apoptosis. The peroxide-sensitive fluorescent probe DCFH-DA was used to measure the intracellular ROS levels. Western blot assay was used to detect the levels of cell cycle and apoptosis related proteins. Xenografts in nude mice were used to evaluate the effect of Sophoridine on pancreatic cancer cell in vivo. RESULTS: Sophoridine killed cancer cells but had low cytotoxicity to normal cells. Pancreatic cancer cells were particularly sensitive. Sophoridine inhibited the proliferation of pancreatic cancer cells and induced cell cycle arrest at S phase and mitochondrial-related apoptosis. Moreover, Sophoridine induced a sustained activation of the phosphorylation of ERK and JNK. In addition, Sophoridine provoked the generation of reactive oxygen species (ROS) in pancreatic cancer cells. Finally, in vivo, Sophoridine suppressed tumor growth in mouse xenograft models. CONCLUSION: These findings suggest Sophoridine is promising to be a novel, potent and selective antitumor drug candidate for pancreatic cancer.


Assuntos
Alcaloides/administração & dosagem , Proliferação de Células/efeitos dos fármacos , Neoplasias Pancreáticas/tratamento farmacológico , Quinolizinas/administração & dosagem , Fase S/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Espécies Reativas de Oxigênio/metabolismo , Fase S/genética , Ensaios Antitumorais Modelo de Xenoenxerto
15.
J Exp Clin Cancer Res ; 36(1): 68, 2017 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-28506239

RESUMO

BACKGROUND: Patients with metastatic or relapsed gallbladder cancer generally have a poor prognosis. Therefore, targeting metastasis is one arm of therapeutic strategies to treat gallbladder cancer. METHODS: Levels of translationally controlled tumor protein (TCTP) were measured in samples of gallbladder cancer by immunohistochemical staining. Wound healing, migration and invasion assays were used to investigate the motility of cells. Western blot assay was used to investigate the levels of TCTP and other proteins. Liver metastasis models and lung metastasis models were established to investigate the inhibitory effect of Dihydroartemisinin on gallbladder cancer metastasis. RESULTS: TCTP is aberrantly expressed in gallbladder cancer patients and associated with metastasis and a poor prognosis. Depleting TCTP significantly inhibited gallbladder cancer cell migration and invasion. We found that Dihydroartemisinin as a potent inhibitor of TCTP inhibited TCTP-dependent cell migration and invasion by reducing cell division control protein 42 homolog (Cdc42) activation. In addition, in mice with xenografted tumors, treatment with Dihydroartemisinin decreased gallbladder cancer cell metastases and improved survival. CONCLUSIONS: These findings provide new insights into the therapeutic activity of Dihydroartemisinin as a treatment for gallbladder cancer metastasis.


Assuntos
Antineoplásicos/farmacologia , Artemisininas/farmacologia , Biomarcadores Tumorais/metabolismo , Neoplasias da Vesícula Biliar/metabolismo , Neoplasias da Vesícula Biliar/patologia , Animais , Biomarcadores Tumorais/genética , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Neoplasias da Vesícula Biliar/genética , Neoplasias da Vesícula Biliar/mortalidade , Xenoenxertos , Humanos , Camundongos , Metástase Neoplásica , Estadiamento de Neoplasias , Proteína cdc42 de Ligação ao GTP/metabolismo
16.
Mol Immunol ; 83: 23-32, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28092804

RESUMO

The IFN-γ production is crucial for NK cell-mediated lysis of cancer cells. Thus increasing the IFN-γ production by NK cells may be an ideal strategy to improve their tumoricidal effect. Since the focus on new drug development has shifted towards natural products, limited information is out there about natural products that enhance the IFN-γ production by NK cells. In this study, through a high-throughput screening, we have identified a natural product ingenol 3,20 dibenzoate (IDB), an activator of tumor suppressor protein kinase C (PKC) isozymes, could increase the IFN-γ production and degranulation by NK cells, especially when NK cells were stimulated by non-small lung cancer (NSCLC) cells. IDB also significantly enhanced the NK cell-mediated lysis of NSCLC cells. Furthermore, PKC inhibitor, sotrastaurin abrogated IDB-induced IFN-γ production, degranulation and cytotoxicity, but did not affect IFN-γ production by NK cells without IDB treatment and NSCLC cell stimulation. The IFN-γ neutralization reversed the IDB-induced enhancement of NK cell mediated killing. In conclusion, our study indicated that IDB enhanced NK cell-mediated lysis of NSCLC cells is dependent on specific PKC mediated IFN-γ production and degranulation. Thus, IDB may have a promising application in clinic for NK cell-based cancer immunotherapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Citotoxicidade Imunológica/efeitos dos fármacos , Diterpenos/farmacologia , Células Matadoras Naturais/efeitos dos fármacos , Neoplasias Pulmonares/patologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Ativação Enzimática/efeitos dos fármacos , Ensaios de Triagem em Larga Escala , Humanos , Interferon gama/biossíntese , Células Matadoras Naturais/imunologia , Neoplasias Pulmonares/imunologia , Proteína Quinase C/metabolismo
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