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1.
J Ethnopharmacol ; : 112645, 2020 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-32045684

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The Coreopsis tinctoria Nutt. flower (CTF) has been used traditionally in China for treating hypertension and diabetes as well as reducing body weight and blood fat. However, the vascular protection effect of the CTF has not been studied to date. AIM OF THE STUDY: This study aimed to screen and identify bioactive fractions from the CTF with a diabetic endothelial protection effect and to clarify the underlying mechanism. MATERIALS AND METHODS: The vascular protection effect of Fraction A was studied in high-fat diet and streptozocin-induced diabetic models. The endothelial protection effect of Fraction A-2 was further studied in an in vitro vascular endothelial dysfunction model induced by high glucose. In a high glucose-induced human umbilical vein endothelial cell (HUVEC) model, Fractions A-2-2 and A-2-3 were screened, and their detailed mechanisms of endothelial protection were studied. Liquid chromatography mass spectrometry (LC-MS) was used to identify the main components in Fractions A-2-2 and A-2-3. RESULTS: Fraction A treatment significantly improved the endothelium-dependent vasodilation of the mesenteric artery induced by acetylcholine in diabetic rats. The maximum relaxation was 79.82 ±â€¯2.45% in the control group, 64.36 ±â€¯9.81% in the model group, and 91.87 ±â€¯7.38% in the Fraction A treatment group (P < 0.01). Fraction A treatment also decreased rat tail pressure compared with the model group at the 12th week. The systolic blood pressure was 152.7 5 ±â€¯16.99 mmHg in the control group, 188.50 ±â€¯5.94 mmHg in the model group, and 172.60 ±â€¯14.31 mmHg in the Fraction A treatment group (P < 0.05). The mean blood pressure was 128.50 ±â€¯13.79 mmHg in the control group, 157.00 ±â€¯6.06 mmHg in the model group, and 144.80 ±â€¯11.97 mmHg in the Fraction A treatment group (P < 0.05). In an in vitro vascular endothelium-dependent vasodilation dysfunction model induced by high glucose, Fraction A-2 improved the vasodilation of the mesenteric artery. The maximum relaxation was 82.15 ±â€¯16.24% in the control group, 73.29 ±â€¯14.25% in the model group, and 79.62 ±â€¯13.89% in the Fraction A-2 treatment group (P < 0.05). In a high glucose-induced HUVEC model, Fraction A-2-2 and Fraction A-2-3 upregulated the expression of IRS-1, Akt, and eNOS and increased the levels of p-IRS-1Ser307, p-Akt Ser473, and p-eNOSSer1177 and also decreased the expression of NOX4, TNF-α, IL-6, sVCAM, sICAM, and NF-κB (P < 0.01). With the intervention of AG490 and LY294002, the above effects of Fraction A-2-2 and Fraction A-2-3 were inhibited (P < 0.01). LC-MS data showed that in Fraction A-2-2 and Fraction A-2-3, there were 10 main components: flavanocorepsin; polyphenolic; flavanomarein; isochlorogenic acid A; dicaffeoylquinic acid; coreopsin; marein; coreopsin; luteolin-7-O-glucoside; and 3',5,5',7-tetrahydroxyflavanone-O-hexoside. CONCLUSION: The protective effect of the CTF on diabetic endothelial dysfunction may be due to its effect on the JAK2/IRS-1/PI3K/Akt/eNOS pathway and the related oxidative stress and inflammation. The results strongly suggested that Fraction A-2-2 and Fraction A-2-3 were the active fractions from the CTF, and the CTF might be a potential option for the prevention of vascular complications in diabetes.

2.
Nat Prod Bioprospect ; 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32016770

RESUMO

A series of dearomatized isoprenylated acylphloroglucinols derivatives, hyperhenols A-E (1-5), as well as seven known analogues (6-12), were characterized from Hypericum henryi. Their structures were determined by combination of NMR, ECD spectroscopy, and X-ray diffraction analysis. Compounds 1 and 6-8 were tested to exhibit potential antitumor properties, of which 6 and 7 inhibited cell growth through inducing apoptosis and cell cycle arrest. In addition, these compounds could induce autophagy and PINK1/Parkin-mediated mitophagy in cancer cell lines, as well as suppress lung cancer A549 cells metastasis in vitro.

3.
Acta Pharmacol Sin ; 41(1): 82-92, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31371781

RESUMO

Metastasis causes the main lethality in esophageal cancer patient. Garcinol, a natural compound extracted from Gambogic genera, is a histone acetyltransferase (HAT) inhibitor that has shown anticancer activities such as cell cycle arrest and apoptosis induction. In this study, we investigated the effects of garcinol on the metastasis of esophageal cancer in vitro and in vivo. We found that garcinol (5-15 µM) dose-dependently inhibited the migration and invasion of human esophageal cancer cell lines KYSE150 and KYSE450 in wound healing, transwell migration, and Matrigel invasion assays. Furthermore, garcinol treatment dose-dependently decreased the protein levels of p300/CBP (transcriptional cofactors and HATs) and p-Smad2/3 expression in the nucleus, thus impeding tumor cell proliferation and metastasis. Knockdown of p300 could inhibit cell metastasis, but CBP knockdown did not affect the cell mobility. It has been reported that TGF-ß1 stimulated the phosphorylation of Smad2/3, which directly interact with p300/CBP in the nucleus, and upregulating HAT activity of p300. We showed that garcinol treatment dose-dependently suppressed TGF-ß1-activated Smad and non-Smad pathway, inhibiting esophageal cancer cell metastasis. In a tail vein injection pulmonary metastasis mouse model, intraperitoneal administration of garcinol (20 mg/kg) or 5-FU (20 mg/kg) significantly decreased the number of lung tumor nodules and the expression levels of Ki-67, p300, and p-Smad2/3 in lung tissues. In conclusion, our study demonstrates that garcinol inhibits esophageal cancer metastasis in vitro and in vivo, which might be related to the suppression of p300 and TGF-ß1 signaling pathways, suggesting the therapeutic potential of Garcinol for metastatic tumors.

4.
Front Oncol ; 9: 586, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31428570

RESUMO

Non-small-cell lung cancer (NSCLC) is the predominant form of lung cancer, and it is regulated by a complex signal transduction network. Single-agent targeted therapy often results in acquired resistance, which leads to treatment failure. In this study, we demonstrated that a combination of the kinase inhibitors trametinib and bosutinib can synergistically suppress the growth of NSCLC by inhibiting both the mitogen-activated protein kinase (MAPK) and proto-oncogene tyrosine-protein kinase (SRC) pathways. The combination was profiled against a panel of 22 NSCLC cell lines, including one erlotinib-resistant cell line, and this combination was found to show synergistic effects against 16 cell lines. NSCLC cell lines (HCC827, HCC827-erlotinib-resistant, and H1650) were treated with trametinib, bosutinib, or a combination of these drugs. The drug combination inhibited colony formation and induced cell apoptosis. A mechanism study showed that the phosphorylation of multiple kinases in the epidermal growth factor receptor (EGFR) signaling pathway in NSCLC was down-regulated. In addition, the combination significantly attenuated tumor growth of HCC827 xenografts with low toxicity. Our findings provide a theoretical basis for further study of the combination of MAPK and SRC pathway inhibitors in NSCLC, especially in the treatment of erlotinib-resistant NSCLC.

5.
Front Oncol ; 9: 654, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31380287

RESUMO

The complexity and multi-target feature of natural compounds have made it difficult to elucidate their mechanism of action (MoA), which hindered the development of lead anticancer compounds to some extent. In this study, we applied RNA-Seq and GSEA transcriptome analysis to rapidly and efficiently evaluate the anticancer mechanisms of neobractatin (NBT), a caged prenylxanthone isolated from the Chinese herb Garcinia bracteata. We found that NBT exerted anti-proliferative effect on various cancer cells and caused both G1/S and G2/M arrest in synchronized cancer cells through its effects on the expression of E2F1 and GADD45α. The in vivo animal study further suggested that NBT could reduce tumor burden in HeLa xenograft model with no apparent toxicity. By demonstrating the biological effect of NBT, we provided evidences for further investigations of this novel natural compound with anticancer potential.

6.
Cell Death Dis ; 10(8): 554, 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31320607

RESUMO

Tumor metastasis is the predominant cause of lethality in cancer. We found that Neobractatin (NBT), a natural compound isolated from Garcinia bracteata, could efficiently inhibit breast and lung cancer cells metastasis. However, the mechanisms of NBT inhibiting cancer metastasis remain unclear. Based on the RNA-sequencing result and transcriptome analysis, Muscleblind-like 2 (MBNL2) was found to be significantly upregulated in the cells treated with NBT. The Cancer Genome Atlas (TCGA) database analysis indicated that the expression of MBNL2 in breast and lung carcinoma tumor tissues was significantly lower compared to normal tissues. We thus conducted to investigate the antimetastatic role of MBNL2. MBNL2 overexpression mimicked the effect of NBT on breast cancer and lung cancer cell motility and metastasis, in addition significantly enhanced the inhibition effect of NBT. MBNL2 knockdown furthermore partially eliminated the inhibitory effect of NBT on metastasis. Mechanistically, we demonstrated that NBT- and MBNL2-mediated antimetastasis regulation significantly correlated with the pAKT/epithelial-mesenchymal transition (EMT) pathway. Subsequent in vivo study showed the same metastasis inhibition effect in NBT and MBNL2 in MDA-MB-231 xenografts mouse model. This study suggest that NBT possesses significant antitumor activity in breast and lung cancer cells that is partly mediated through the MBNL2 expression and enhancement in metastasis via the pAKT/EMT signaling pathway.

7.
Pharmacol Res ; 147: 104328, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31288080

RESUMO

A global transcriptional regulator, MgrA, was previously identified as a key determinant of virulence in Staphylococcus aureus. An 80% EtOH extract of Uncaria gambier was found to attenuate the virulence of S. aureus via its effects on MgrA. Using bioassay-guided fractionation, a polyphenolic polymer, uncariitannin, was found to be the main bioactive constituent of the extract, and its structure was characterized using spectral and chemical analysis. The molecular weight and polydispersity of uncariitannin were determined by gel permeation chromatography-refractive index-light scattering analysis. An electrophoretic mobility shift assay showed that uncariitannin could effectively inhibit the interaction of MgrA with DNA in a dose-dependent manner. Treatment with uncariitannin could decrease the mRNA and protein levels of Hla in both the S. aureus Newman and USA300 LAC strains. Further analysis of Hla expression levels in the Newman ΔmgrA and Newman ΔmgrA/pYJ335-mgrA strains indicated that uncariitannin altered Hla expression primarily in an MgrA-dependent manner. A mouse model of infection indicated that uncariitannin could attenuate MRSA virulence. In conclusion, uncariitannin may be a potential candidate for further development as an antivirulence agent for the treatment of S. aureus infection.

8.
Org Lett ; 21(5): 1534-1537, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30775925

RESUMO

Garsubelone A (1), the first dimeric polycyclic polyprenylated acylphloroglucinols type metabolite featuring a complicated 6/6/6/6/6/6/6 heptacyclic architecture containing 10 stereogenic centers, was isolated from Garcinia subelliptica. Biogenetically, this compound was constructed by the plausible monomeric precursor, garsubelone B (2) and secohyperforin, via a key Diels-Alder cycloaddition to form an unique 2-oxabicyclo[3.3.1]nonane core. Their structures and absolute configurations were determined by comprehensive spectroscopic and X-ray diffraction techniques. The cytotoxic activities of these isolates were also evaluated.


Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/metabolismo , Garcinia/química , Floroglucinol/análogos & derivados , Compostos Policíclicos/química , Compostos Policíclicos/metabolismo , Terpenos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura Molecular , Floroglucinol/química , Compostos Policíclicos/isolamento & purificação , Difração de Raios X
9.
Acta Pharmacol Sin ; 40(7): 919-928, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30315250

RESUMO

Autophagy, a form of cellular self-digestion by lysosome, is associated with various disease processes including cancers, and modulating autophagy has shown promise in the treatment of various malignancies. A number of natural products display strong antitumor activity, yet their mechanisms of action remain unclear. To gain a better understanding of how traditional Chinese medicine agents exert antitumor effects, we screened 480 natural compounds for their effects on autophagy using a high content screening assay detecting GFP-LC3 puncta in HeLa cells. Tubeimoside-1 (TBMS1), a triterpenoid saponin extracted from Bolbostemma paniculatum (Maxim) Franquet (Cucurbitaceae), was identified as a potent activator of autophagy. The activation of autophagy by TBMS1 was evidenced by increased LC3-II amount and GFP-LC3 dots, observation of autophagosomes under electron microscopy, and enhanced autophagic flux. To explore the mechanisms underlying TBMS1-activated autophagy, we performed cheminformatic analyses and surface plasmon resonance (SPR) binding assay that showed a higher likelihood of the binding between Akt protein and TBMS1. In three human breast cancer cell lines, we demonstrated that Akt-mTOR-eEF-2K pathway was involved in TBMS1-induced activation of autophagy, while Akt-mediated downregulations of Mcl-1, Bcl-xl, and Bcl-2 led to the activation of apoptosis of the breast cancer cells. Inhibition of autophagy enhanced the cytotoxic effect of TBMS1 via promoting apoptosis. Our results demonstrate the role and mechanism of TBMS1 in activating autophagy, suggesting that inhibition of cytoprotective autophagy may act as a therapeutic strategy to reinforce the activity of TBMS1 against cancers.


Assuntos
Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Saponinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Triterpenos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo
10.
Acta Pharmacol Sin ; 40(7): 929-937, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30333555

RESUMO

Lysosomes are the terminal organelles of the autophagic-endocytic pathway and play a key role in the degradation of autophagic contents. We previously reported that a natural compound oblongifolin C (OC) increased the number of autophagosomes and impaired the degradation of P62, most likely via suppression of lysosomal function and blockage of autophagosome-lysosome fusion. However, the precise mechanisms of how OC inhibits the lysosome-autophagy pathway remain unclear. In the present study, we investigated the effect of OC on transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, lysosomal function and autophagy. We showed that treatment with OC (15 µM) markedly enhanced the nuclear translocation of TFEB in HeLa cells, concomitantly reduced the interaction of TFEB with 14-3-3 proteins. We further demonstrated that OC caused significant inhibition of mTORC1 along with TFEB nuclear translocation, and OC-mediated TFEB nuclear translocation was dependent on mTORC1 suppression. Intriguingly, this increased nuclear TFEB was accompanied by reduced TFEB luciferase activity, increased lysosomal pH and impaired cathepsin enzyme activities. In HeLa cells, treatment with OC (7.5 µM) resulted in about 30% of cell death, whereas treatment with hydroxycitrate, a caloric restriction mimetic (20 µM) did not affect the cell viability. However, cotreatment with OC and hydroxycitrate caused significantly great cytotoxicity (>50%). Taken together, these results demonstrate that inhibition of lysosome function is mediated by OC, despite evident TFEB nuclear translocation.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Lisossomos/metabolismo , Transporte Proteico/efeitos dos fármacos , Terpenos/farmacologia , Animais , Antineoplásicos/farmacologia , Autofagossomos/metabolismo , Autofagia/efeitos dos fármacos , Núcleo Celular/metabolismo , Citratos/farmacologia , Frutas/química , Garcinia/química , Células HeLa , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Terpenos/isolamento & purificação
12.
EBioMedicine ; 37: 344-355, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30348622

RESUMO

BACKGROUND: The pharmacological activation of thermogenesis in brown adipose tissue has long been considered promising strategies to treat obesity. However, identification of safe and effective agents remains a challenge. In this study, we addressed this challenge by developing a cellular system with a fluorescence readout, and applied in a high-throughput manner to screen for FDA-approved drugs that may activate endogenous UCP1 expression in adipocytes. METHODS: We have generated a Ucp1-2A-GFP reporter mouse, in which GFP intensity serves as a surrogate of the endogenous expression level of UCP1 protein; and immortalized brown adipocytes were derived from this mouse model and applied in drug screening. Candidate drugs were further tested in mouse models either fed with normal chow or high fat diet to induce obesity. FINDINGS: By using the cellular screening platform, we identified a group of FDA-approved drugs that can upregulate UCP1 expression in brown adipocyte, including previously known UCP1 activators and new candidate drugs. Further studies focusing on a previously unreported drug-sutent, revealed that sutent treatment could increase the energy expenditure and inhibit lipid synthesis in mouse adipose and liver tissues, resulting in improved metabolism and resistance to obesity. INTERPRETATION: This study offered an easy-to-use cellular screening system for UCP1 activators, and provided a candidate list of FDA-approved drugs that can potentially treat obesity. Further study of these candidates may shed new light on the drug discovery towards obesity. FUND: National Key Research and Development Program and the Strategic Priority Research Program of the Chinese Academy of Sciences, etc. (250 words).


Assuntos
Adipócitos Marrons/metabolismo , Tecido Adiposo Marrom/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Proteína Desacopladora 1/biossíntese , Adipócitos Marrons/patologia , Tecido Adiposo Marrom/patologia , Animais , Linhagem Celular Transformada , Aprovação de Drogas , Avaliação Pré-Clínica de Medicamentos , Camundongos , Camundongos Transgênicos , Proteína Desacopladora 1/genética , Estados Unidos , United States Food and Drug Administration
13.
Cell Death Dis ; 9(5): 538, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29749405

RESUMO

Gemcitabine (GEM)-induced drug resistance is the major reason for the failure of chemotherapy in pancreatic cancer (PC). In this study, we found that Oblongifolin C (OC) efficiently inhibited PC cell proliferation by inducing G0/G1 arrest and apoptosis. Also, our mechanism study demonstrated that OC re-sensitized the GEM-resistant PC cells through the ubiquitin-proteasome-dependent degradation of Src, and then downregulating the MAPK pathway. Knockdown of Src plus OC resulted in a greater inhibitory effect in GEM-resistant PC cells. In contrast, Src overexpression reversed OC-mediated chemosensitization, thereby implicating Src in the action of OC. Moreover, our in vivo study showed that OC suppressed the tumor growth via the downregulation of Src, and enhanced the chemosensitivity of GEM-resistant PC to GEM. Overall, our results have revealed that OC is applicable as a promising agent for overcoming GEM-resistant PC, especially with aberrant Src expression.


Assuntos
Desoxicitidina/análogos & derivados , Regulação para Baixo/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neoplasias Pancreáticas , Terpenos/farmacologia , Animais , Linhagem Celular Tumoral , Desoxicitidina/farmacologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Cell Death Dis ; 9(3): 262, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29449529

RESUMO

Erlotinib resistance causes a high degree of lethality in non-small-cell lung cancer (NSCLC) patients. The high expression and activation of several receptor tyrosine kinases, such as JAK/STAT3, c-Met, and EGFR, play important roles in drug resistance. The development of tyrosine kinase inhibitors is urgently required in the clinic. Our previous study found that Gambogenic acid (GNA), a small molecule derived from the traditional Chinese medicine herb gamboge, induced cell death in several NSCLC cell lines through JAK/STAT3 inhibition. In this study, we investigated the mechanism of action of GNA in erlotinib-resistant NSCLC and patient-derived cells. The inhibition of GNA on FGFR signaling pathway was examined using biochemical kinase assays. NSCLC cell lines (HCC827, HCC827-Erlotinib-resistant, and H1650) and primary cells from patients with NSCLC with clinical resistance to erlotinib were treated with GNA, erlotinib, or their combination. Both kinase assays and cell- based assays showed that GNA inhibits the phosphorylation of multiple kinases in FGFR signaling pathway in NSCLC. The combination of GNA and erlotinib significantly attenuates the tumor growth of HCC827 and erlotinib-resistant HCC827 xenografts with low toxicity. Importantly, GNA significantly suppresses tumor growth in a lung patient-derived xenograft (PDX) model with FGFR fusion and low EGFR expression. Our findings provide preclinical evidence for using GNA as an FGFR signaling pathway inhibitor to overcome erlotinib resistance in NSCLC treatment or to enhance erlotinib efficacy when used as a combined administration.

15.
Curr Protein Pept Sci ; 19(4): 380-388, 2018 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-28059040

RESUMO

The epidermal growth factor receptor (EGFR) belongs to ErbB family of tyrosine kinases, which plays an important role in the regulation of cell proliferation, survival, differentiation, and metastasis. In addition, tumors develop resistance to EGFR inhibitors due to the presence or development of point mutations in the tyrosine kinase domain of the receptor. There is an urgent need to develop new anti-EGFR agents with strong therapeutic activities. As the majority of anticancer drugs are of natural origin, natural products are a valuable source for the identification and development of novel treatment options for cancer. To identify promising new anti-tumor agents that act on the EGFR, numerous studies have been carried out and some investigators found natural products that could effectively inhibit the EGFR. This review summarizes the latest developments related to anti- EGFR agents derived from natural compounds and traditional Chinese medicine (TCM).


Assuntos
Antineoplásicos/química , Produtos Biológicos/química , Receptores ErbB/metabolismo , Animais , Antineoplásicos/farmacologia , Produtos Biológicos/farmacologia , Proliferação de Células , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Humanos , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais
16.
Theranostics ; 7(18): 4566-4576, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29158845

RESUMO

Inhibition of the interaction between p53 and MDM2/MDMX has attracted significant attention in anticancer therapy development. We designed a series of in-tether chiral center-induced helical stabilized peptides, among which MeR/PhR effectively reactivated p53. The activation of p53 inhibits cell proliferation and induces apoptosis in both the MCF-7 normal tumor cell line and the PA-1 pluripotent cancer cell line with only minimal cellular toxicity towards normal cells or cancer cell lines with p53 mutations. The in vivo bioactivity study of the peptide in the ovarian teratocarcinoma (PA-1) xenograft model showed a tumor growth rate inhibition of 70% with a dosage of 10 mg/kg (one injection every other day). This is the first application of a stabilized peptide modulator targeting stem-like cancer cell both in vitro and in vivo and provides references to cancer stem cell therapy.


Assuntos
Células-Tronco Neoplásicas/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/genética , Western Blotting , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Feminino , Células HCT116 , Humanos , Imunoprecipitação , Células MCF-7 , Microscopia Confocal , Mutação/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Peptídeos/química , Peptídeos/farmacologia , Ubiquitinação
17.
Acta Pharmacol Sin ; 38(2): 252-263, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27840412

RESUMO

Oblongifolin C (OC) and guttiferone K (GUTK) are two anticancer compounds extracted from Garcinia yunnanensis Hu, but they act by different mechanisms. In this study we investigated whether a combination of OC and GUTK (1:1 molar ratio) could produce synergistic anticancer effects against human colorectal cancer cells in vitro. For comparison, we also examined the anticancer efficacy of ethanol extracts from G yunnanensis fruit, which contain OC and GUTK up to 5%. Compared to OC and GUTK alone, the combination of OC and GUTK as well as the ethanol extracts more potently inhibited the cancer cell growth with IC50 values of 3.4 µmol/L and 3.85 µg/mL, respectively. Furthermore, OC and GUTK displayed synergistic inhibition on HCT116 cells: co-treatment with OC and GUTK induced more prominent apoptosis than treatment with either drug alone. Moreover, the combination of OC and GUTK markedly increased cleavage of casapse-3 and PARP, and enhanced cellular ROS production and increased JNK protein phosphorylation. In addition, the combination of OC and GUTK exerted stronger effects under nutrient-deprived conditions than in complete medium, suggesting that autophagy played an essential role in regulating OC- and GUTK-mediated cell death. OC and GUTK are the main components that contribute to the anticancer activity of G yunnanensis and the compounds have apoptosis-inducing effects in HCT116 cells in vitro.


Assuntos
Apoptose/efeitos dos fármacos , Benzofenonas/farmacologia , Garcinia/química , Terpenos/farmacologia , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Benzofenonas/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Frutas/química , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Terpenos/isolamento & purificação
19.
Molecules ; 21(10)2016 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-27754347

RESUMO

Nujiangexathone A (NJXA), a novel compound derived from Garcinia nujiangensis, has been demonstrated to inhibit the proliferation of several human cancer cell lines. This study is the first to demonstrate the apoptosis inductive activities of NJXA and the possible underlying mechanisms. Our results demonstrated that NJXA inhibited colony formation by HeLa and SiHa cells in a dose-dependent manner. An Annexin V-FITC/PI staining assay showed that NJXA strongly triggered apoptosis in a dose-dependent manner. Western blotting analyses showed that NJXA induced the caspase-dependent apoptosis of HeLa and SiHa cells by triggering a series of events, including changes in the levels of Bcl-2 family proteins, cytochrome c release, caspase-3 activation, and chromosome fragmentation. Furthermore, we demonstrated that NJXA induced cell apoptosis by activating the reactive oxygen species (ROS)-mediated JNK signaling pathway. Consistent with this finding, a ROS scavenger, N-acetyl-l-cysteine (NAC, 10 mM), hindered NJXA-induced apoptosis and attenuated the sensitivity of HeLa and SiHa cells to NJXA. In vivo results further confirmed that the tumor inhibitory effect of NJXA was partially through the induction of apoptosis. Taken together, our results demonstrated that NJXA induced the apoptosis of HeLa and SiHa cells through the ROS/JNK signaling pathway, indicating that NJXA could be important candidate for the clinical treatment of cervical cancer.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Caspases/metabolismo , Garcinia/química , Extratos Vegetais/administração & dosagem , Neoplasias do Colo do Útero/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/farmacologia , Apoptose , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HeLa , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Extratos Vegetais/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Neoplasias do Colo do Útero/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Sci Rep ; 6: 35789, 2016 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-27767059

RESUMO

A UPLC-PDA-QTOFMS-guided isolation strategy was employed to screen and track potentially new compounds from Garcinia oblongifolia. As a result, two new prenylated xanthones, oblongixanthones D and E (1-2), six new prenylated benzoylphloroglucinol derivatives, oblongifolins V-Z (3-7) and oblongifolin AA (8), as well as a known compound oblongifolin L (9), were isolated from the EtOAc-soluble fraction of an acetone extract of the leaves of Garcinia oblongifolia guided by UPLC-PDA-QTOFMS analysis. The structures of the new compounds were elucidated by 1D- and 2D-NMR spectroscopic analysis and mass spectrometry. Experimental and calculated ECD spectra were used to determine the absolute configurations. The results of wound healing and transwell migration assay showed that oblongixanthones D (1), E (2), and oblongifolin L (9) have the ability to inhibit cancer cell migration in lower cytotoxic concentrations. Western blotting results showed that these compounds exhibited an anti-metastasis effect mainly through downregulating RAF protein levels. In addition, 2 and 9 could inhibit phospho-MEK and phospho-ERK at downstream. Moreover, 1, 2, and 9 could inhibit snail protein level, suggesting that they could regulate the EMT pathway.


Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Inibição de Migração Celular/efeitos dos fármacos , Garcinia/química , Floroglucinol/análogos & derivados , Xantonas/isolamento & purificação , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Ensaios de Seleção de Medicamentos Antitumorais , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Células Hep G2 , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Floroglucinol/química , Floroglucinol/isolamento & purificação , Folhas de Planta/química , Prenilação , Espectrometria de Massas por Ionização por Electrospray , Xantonas/química , Xantonas/farmacologia
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