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1.
Int J Mol Sci ; 24(13)2023 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-37446120

RESUMO

Autophagy plays a complex impact role in tumor initiation and development. It serves as a double-edged sword by supporting cell survival in certain situations while also triggering autophagic cell death in specific cellular contexts. Understanding the intricate functions and mechanisms of autophagy in tumors is crucial for guiding clinical approaches to cancer treatment. Recent studies highlight its significance in various aspects of cancer biology. Autophagy enables cancer cells to adapt to and survive unfavorable conditions by recycling cellular components. However, excessive or prolonged autophagy can lead to the self-destruction of cancer cells via a process known as autophagic cell death. Unraveling the molecular mechanisms underlying autophagy regulation in cancer is crucial for the development of targeted therapeutic interventions. In this review, we seek to present a comprehensive summary of current knowledge regarding autophagy, its impact on cancer cell survival and death, and the molecular mechanisms involved in the modulation of autophagy for cancer therapy.


Assuntos
Autofagia , Neoplasias , Humanos , Morte Celular Autofágica , Autofagia/efeitos dos fármacos , Autofagia/fisiologia , Sobrevivência Celular , Transformação Celular Neoplásica , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico
2.
Acta Pharmacol Sin ; 42(2): 199-208, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32759963

RESUMO

Mitophagy is a selective form of autophagy involving the removal of damaged mitochondria via the autophagy-lysosome pathway. PINK1-Parkin-mediated mitophagy is one of the most important mechanisms in cardiovascular disease, cerebral ischemia-reperfusion (I/R) injury, and neurodegenerative diseases. In this study we conducted an image-based screening in YFP-Parkin HeLa cells to discover new mitophagy regulators from natural xanthone compounds. We found that garciesculenxanthone B (GeB), a new xanthone compound from Garcinia esculenta, induced the formation of YFP-Parkin puncta, a well known mitophagy marker. Furthermore, treatment with GeB dose-dependently promoted the degradation of mitochondrial proteins Tom20, Tim23, and MFN1 in YFP-Parkin HeLa cells and SH-SY5Y cells. We revealed that GeB stabilized PINK1 and triggered Parkin translocation to the impaired mitochondria to induce mitophagy, and these effects were abolished by knockdown of PINK1. Finally, in vivo experiments demonstrated that GeB partially rescued ischemia-reperfusion-induced brain injury in mice. Taken together, our findings demonstrate that the natural compound GeB can promote the PINK1-Parkin-mediated mitophagy pathway, which may be implicated in protection against I/R brain injury.


Assuntos
Isquemia Encefálica/prevenção & controle , Garcinia/química , Traumatismo por Reperfusão/prevenção & controle , Xantonas/farmacologia , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Técnicas de Silenciamento de Genes , Células HeLa , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Mitofagia/efeitos dos fármacos , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Xantonas/administração & dosagem , Xantonas/isolamento & purificação
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.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Proteína p300 Associada a E1A/metabolismo , Neoplasias Esofágicas/tratamento farmacológico , Garcinia/química , Transdução de Sinais/efeitos dos fármacos , Terpenos/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Proteína p300 Associada a E1A/deficiência , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Terpenos/química , Terpenos/isolamento & purificação , Células Tumorais Cultivadas , Cicatrização/efeitos dos fármacos
4.
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.


Assuntos
Antibacterianos , Polímeros , Polifenóis , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Uncaria , Virulência/efeitos dos fármacos , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Toxinas Bacterianas/genética , Toxinas Bacterianas/metabolismo , Feminino , Proteínas Hemolisinas/genética , Proteínas Hemolisinas/metabolismo , Rim/efeitos dos fármacos , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Camundongos Endogâmicos BALB C , Miocárdio/patologia , Polímeros/farmacologia , Polímeros/uso terapêutico , Polifenóis/farmacologia , Polifenóis/uso terapêutico , Baço/efeitos dos fármacos , Baço/patologia , Infecções Estafilocócicas/patologia , Staphylococcus aureus/genética , Staphylococcus aureus/metabolismo , Staphylococcus aureus/patogenicidade
5.
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
6.
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
7.
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
8.
Bioorg Med Chem ; 24(18): 4120-4128, 2016 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-27396929

RESUMO

Oblongifolin C, one of the polyprenylated benzoylphloroglucinol natural products (PPAPs) isolated from the fruits of Garcinia yunnanensis Hu, was recently discovered to be a potent anti-tumor agent. A collection of 12 derivatives with modifications on the benzophenone moieties were synthesized and tested for c-Met kinase inhibition and cytotoxicity against the HepG2, Miapaca-2, HCC827, Hela, A549, AGS, and HT-29 cell lines in vitro. An oxidized derivative, 10, was found to possess strong inhibition and anti-migration properties in the HCC827 cell line and serves as a potential lead compound for the development of new anticancer drugs. In addition, structure-activity relationships (SAR) were also evaluated to provide key information for future anticancer drug development.


Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Terpenos/química , Terpenos/farmacologia , Antineoplásicos Fitogênicos/síntese química , Benzofenonas/síntese química , Benzofenonas/química , Benzofenonas/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Garcinia/química , Células HT29 , Células HeLa , Humanos , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Relação Estrutura-Atividade , Terpenos/síntese química
9.
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
10.
Angew Chem Int Ed Engl ; 55(39): 12088-93, 2016 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-27572954

RESUMO

Described is a facile helix-nucleating template based on a tethered aspartic acid at the N-terminus [terminal aspartic acid (TD)]. The nucleating effect of the template is subtly influenced by the substituent at the end of the side-chain-end tether as indicated by circular dichroism, nuclear magnetic resonance, and molecular dynamics simulations. Unlike most nucleating strategies, the N-terminal amine is preserved, thus enabling further modification. Peptidomimetic estrogen receptor modulators (PERMs) constructed using this strategy show improved therapeutic properties. The current strategy can be regarded as a good complement to existing helix-stabilizing methods.

11.
Biochem Biophys Res Commun ; 457(3): 300-6, 2015 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-25576357

RESUMO

A key clinical problem in oncology is the treatment of apoptosis-resistant tumors. Tumor cells deficient in both of the proapoptotic proteins Bax and Bak are protected against most chemotherapeutic drug-induced apoptosis. We report here that a natural compound, oblongifolin C (OC), effectively eliminates Bax/Bak-deficient murine embryonic fibroblasts and colon carcinoma HCT116 cells. OC not only triggers DNA double-strand breaks and DNA damage response, but also inhibits repair of DNA damage. In addition, OC induces ER stress through upregulation of the transcription factor CHOP and activation of JNK kinases. Upon treatment with OC, cells undergo Bax/Bak-independent, caspase-mediated apoptosis. Taken together, our data establish a rationale for the broad use of OC to treat apoptosis deficient tumors.


Assuntos
Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Dano ao DNA , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Terpenos/farmacologia , Proteína Killer-Antagonista Homóloga a bcl-2/deficiência , Proteína X Associada a bcl-2/deficiência , Animais , Antineoplásicos Fitogênicos/farmacologia , Caspases/metabolismo , Células Cultivadas , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Quebras de DNA de Cadeia Dupla , Reparo do DNA/efeitos dos fármacos , Células HCT116 , Humanos , Camundongos , Camundongos Knockout , Proteína Killer-Antagonista Homóloga a bcl-2/genética , Proteína X Associada a bcl-2/genética
12.
BMC Cancer ; 15: 254, 2015 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-25885018

RESUMO

BACKGROUND: In a cytotoxicity screen in serum-free medium, Guttiferone F showed strong growth inhibitory effect against prostate cancer cells. METHODS: Prostate cancer cells LNCaP and PC3 were treated with Guttiferone F in serum depleted medium. Sub-G1 phase distributions were estimated with flow cytometry. Mitochondrial disruption was observed under confocal microscope using Mitotracker Red staining. Gene and protein expression changes were detected by real-time PCR and Western blotting. Ca(2+) elevation was examined by Fluo-4 staining under fluorescence microscope. PC3 xenografts in mice were examined by immunohistochemical analysis. RESULTS: Guttiferone F had strong growth inhibitory effect against prostate cancer cell lines under serum starvation. It induced a significant increase in sub-G1 fraction and DNA fragmentation. In serum-free medium, Guttiferone F triggered mitochondria dependent apoptosis by regulating Bcl-2 family proteins. In addition, Guttiferone F attenuated the androgen receptor expression and phosphorylation of ERK1/2, while activating the phosphorylation of JNK and Ca(2+) flux. Combination of caloric restriction with Guttiferone F in vivo could increase the antitumor effect without causing toxicity. CONCLUSIONS: Guttiferone F induced prostate cancer cell apoptosis under serum starvation via Ca(2+) elevation and JNK activation. Combined with caloric restriction, Guttiferone F exerted significant growth inhibition of PC3 cells xenograft in vivo. Guttiferone F is therefore a potential anti-cancer compound.


Assuntos
Apoptose/efeitos dos fármacos , Benzofenonas/farmacologia , Produtos Biológicos/farmacologia , Cálcio/metabolismo , Restrição Calórica , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Neoplasias da Próstata/metabolismo , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Benzofenonas/administração & dosagem , Benzofenonas/química , Produtos Biológicos/administração & dosagem , Produtos Biológicos/química , Caspases/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Citosol/metabolismo , Modelos Animais de Doenças , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptores Androgênicos/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Planta Med ; 81(1): 79-89, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25478784

RESUMO

Natural compounds from medicinal plants are important resources for drug development. Active compounds targeting apoptosis and autophagy are candidates for anti-cancer drugs. In this study, we collected Garcinia species from China and extracted them into water or ethanol fractions. Then, we performed a functional screen in search of novel apoptosis and autophagy regulators. We first characterized the anti-proliferation activity of the crude extracts on multiple cell lines. HeLa cells expressing GFP-LC3 were used to examine the effects of the crude extracts on autophagy. Their activities were confirmed by Western blots of A549 and HeLa cells. By using bioassay guided fractionation, we found that two caged prenylxanthones from Garcinia bracteata, neobractatin and isobractatin, can significantly induce apoptosis and inhibit autophagy. Our results suggest that different Garcinia species displayed various degrees of toxicity on different cancer cell lines. Furthermore, the use of a high content screening assay to screen natural products was an essential method to identify novel autophagy regulators.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Garcinia/química , Antineoplásicos Fitogênicos/química , Linhagem Celular Tumoral/efeitos dos fármacos , China , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Células HeLa , Humanos , Plantas Medicinais/química , Xantonas/química , Xantonas/farmacologia
14.
Mediators Inflamm ; 2015: 350564, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26538826

RESUMO

Garcinia Linn. plants having rich natural xanthones and benzophenones with anti-inflammatory activity attracted a great deal of attention to discover and develop them as potential drug candidates. Through screening targeting nitric oxide accumulation in stimulated macrophage, we found that 1,3,5,7-tetrahydroxy-8-isoprenylxanthone (TIE) had potential anti-inflammatory effect. To understand how TIE elicits its anti-inflammatory activity, we uncovered that it significantly inhibits the production of nitric oxide (NO) and prostaglandin E2 (PGE2) in LPS/IFNγ-stimulated RAW264.7 cells. In further study, we showed that TIE reduced the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), two key molecules responsible for the production of NO and PGE2 during inflammation progress. Additionally, TIE also suppressed the expression of inflammatory cytokines IL-6, IL-12, and TNF-α. TIE-led suppression in iNOS, COX-2, and cytokines production were probably the consequence of TIE's capability to block ERK and p38MAPK signaling pathway. Moreover, TIE blocked activation of nuclear factor-kappa B (NF-κB) as well as NF-κB regulation of miR155 expression. Our study suggests that TIE may represent as a potential therapeutic agent for the treatment of inflammatory diseases.


Assuntos
Anti-Inflamatórios/farmacologia , Garcinia/química , Macrófagos/efeitos dos fármacos , Extratos Vegetais/química , Xantonas/farmacologia , Animais , Sobrevivência Celular , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Inflamação , Interleucina-6/metabolismo , Lipopolissacarídeos/química , Camundongos , NF-kappa B/metabolismo , Óxido Nítrico/química , Óxido Nítrico Sintase Tipo II/metabolismo , Células RAW 264.7 , Transdução de Sinais , Xantonas/isolamento & purificação , Xantonas/uso terapêutico
15.
Molecules ; 20(6): 11387-99, 2015 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-26102071

RESUMO

Two new xanthones, cowaxanthones G (1) and H (2), and 23 known analogues were isolated from an acetone extract of the leaves of Garcinia cowa. The isolated compounds were evaluated for cytotoxicity against three cancer cell lines and immortalized HL7702 normal liver cells, whereby compounds 1, 5, 8, and 15-17 exhibited significant cytotoxicity. Cell cycle analysis using flow cytometry showed that 5 induced cell cycle arrest at the S phase in a dose-dependent manner, 1 and 16 at the G2/M phase, and 17 at the G1 phase, while 16 and 17 induced apoptosis. Moreover, autophagy analysis by GFP-LC3 puncta formation and western blotting suggested that 17 induced autophagy. Taken together, our results suggest that these xanthones possess anticancer activities targeting cell cycle, apoptosis, and autophagy signaling pathways.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Extratos Vegetais/administração & dosagem , Xantonas/administração & dosagem , Linhagem Celular Tumoral , Garcinia/química , Humanos , Extratos Vegetais/química , Folhas de Planta/química , Xantonas/química , Xantonas/isolamento & purificação
16.
Biochem Biophys Res Commun ; 451(2): 322-8, 2014 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-25091479

RESUMO

Mcl-1 is a major anti-apoptotic Bcl-2 family protein. It is well known that Mcl-1 can interact with certain pro-apoptotic Bcl-2 family proteins in normal cells to neutralize their pro-apoptotic functions, thus prevent apoptosis. In addition, it was recently found that Mcl-1 can also inhibit mitochondrial calcium uptake. The detailed mechanism, however, is still not clear. Based on Yeast Two-Hybrid screening and co-immunoprecipitation, we identified a mitochondrial protein p32 (C1qbp) as a novel binding partner of Mcl-1. We found that p32 had a number of interesting properties: (1) p32 can positively regulate UV-induced apoptosis in HeLa cells. (2) Over-expressing p32 could significantly promote mitochondrial calcium uptake, while silencing p32 by siRNA suppressed it. (3) In p32 knockdown cells, Ruthenium Red treatment (an inhibitor of mitochondrial calcium uniporter) showed no further suppressive effect on mitochondrial calcium uptake. In addition, in Ruthenium Red treated cells, Mcl-1 also failed to suppress mitochondrial calcium uptake. Taken together, our findings suggest that p32 is part of the putative mitochondrial uniporter that facilitates mitochondrial calcium uptake. By binding to p32, Mcl-1 can interfere with the uniporter function, thus inhibit the mitochondrial Ca(2+) uploading. This may provide a novel mechanism to explain the anti-apoptotic function of Mcl-1.


Assuntos
Apoptose/fisiologia , Cálcio/metabolismo , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Apoptose/efeitos da radiação , Proteínas Reguladoras de Apoptose/metabolismo , Canais de Cálcio/metabolismo , Proteínas de Transporte , Técnicas de Silenciamento de Genes , Células HeLa , Humanos , Proteínas Mitocondriais/antagonistas & inibidores , Proteínas Mitocondriais/genética , Modelos Biológicos , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Estabilidade Proteica , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Interferente Pequeno/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Técnicas do Sistema de Duplo-Híbrido , Raios Ultravioleta
17.
J Nat Prod ; 77(7): 1700-7, 2014 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-24960143

RESUMO

Five new prenylated benzoylphloroglucinol derivatives, garciesculentones A-E (1-5), a new xanthone, garciesculenxanthone A (6), and 15 known compounds were isolated from the petroleum ether extract and the EtOAc-soluble fraction of a 80% (v/v) EtOH extract of Garcinia esculenta. The structures of the new compounds were elucidated by 1D- and 2D-NMR spectroscopic analysis and mass spectrometry. Experimental and calculated ECD and a convenient modified Mosher's method were used to determine the absolute configurations. The cytotoxicity of these compounds were evaluated by MTT assay against three human cancer cell lines (HepG2, MCF-7, and MDA-MB-231) and against normal hepatic cells (HL-7702). In addition, these isolates were evaluated for their inhibitory effects on interferon-γ plus lipopolysaccharide-induced nitric oxide production in RAW264.7 cells.


Assuntos
Anti-Inflamatórios , Antineoplásicos Fitogênicos , Medicamentos de Ervas Chinesas , Garcinia/química , Floroglucinol , Xantonas , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/farmacologia , Feminino , Células Hep G2 , Humanos , Interferon gama/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Óxido Nítrico/biossíntese , Ressonância Magnética Nuclear Biomolecular , Floroglucinol/análogos & derivados , Floroglucinol/química , Floroglucinol/isolamento & purificação , Floroglucinol/farmacologia , Prenilação , Xantonas/química , Xantonas/isolamento & purificação , Xantonas/farmacologia
18.
Virol J ; 10: 333, 2013 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-24220021

RESUMO

BACKGROUND: An animal model for HBV that more closely approximates the disease in humans is needed. The tree shrew (Tupaia belangeri) is closely related to primates and susceptible to HBV. We previously established that neonatal tree shrews can be persistently infected with HBV in vivo, and here present a six year follow-up histopathological study of these animals. METHODS: Group A consists of six tree shrews with persistent HBV infection, group B consists of three tree shrews with suspected persistent HBV infection, while group C consists of four tree shrews free of HBV infection. Serum and liver tissues samples were collected periodically from all animals. HBV antigen and HBV antibodies were detected by ELISA and/or TRFIA. HBV DNA in serum and in liver biopsies was measured by FQ-PCR. Liver biopsies were applied for general histopathologic observation and scoring, immunohistochemical detections of HBsAg and HBcAg, and ultrastructural observation with electron microscope technique. RESULTS: Hydropic, fatty and eosinophilic degeneration of hepatocytes, lymphocytic infiltration and hyperplasia of small bile ducts in the portal area were observed in group A. One animal infected with HBV for over six years showed multiple necrotic areas which had fused to form bridging necrosis and fibrosis, and megalocytosis. The hepatic histopathological scores of group A were higher than those of group B and C. The histopathological score correlated positively with the duration of infection. CONCLUSIONS: Hepatic histopathological changes observed in chronically HBV-infected tree shrews are similar to those observed in HBV-infected humans. The tree shrew may represent a novel animal model for HBV infection.


Assuntos
Vírus da Hepatite B/isolamento & purificação , Hepatite B/patologia , Fígado/patologia , Animais , DNA Viral/análise , DNA Viral/genética , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Anticorpos Anti-Hepatite B/sangue , Antígenos da Hepatite B/sangue , Histocitoquímica , Humanos , Imuno-Histoquímica , Microscopia , Reação em Cadeia da Polimerase , Tupaiidae
19.
J Nat Prod ; 75(8): 1459-64, 2012 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-22871217

RESUMO

Bioassay-guided fractionation of the acetone extract of the leaves of Garcinia nujiangensis resulted in the isolation of two new prenylated xanthones, nujiangexanthones A (1) and B (2), three new polycyclic polyprenylated acylphloroglucinols, nujiangefolins A-C (3-5), and 10 known related analogues. The structures of compounds 1-5 were elucidated by interpretation of their spectroscopic data. Compounds 3 and 4 are unusual polycyclic polyprenylated acylphloroglucinols in which the enol hydroxy group forms a six-membered ring with a benzene ring carbon. The compounds isolated were evaluated for their cytotoxic effects against 11 cancer cell lines and immortalized MIHA normal liver cells, and the test substances demonstrated selectivity toward the cancer cells. Isojacareubin (6) was found to be the most potent cytotoxic compound of those tested.


Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Medicamentos de Ervas Chinesas/isolamento & purificação , Garcinia/química , Floroglucinol/análogos & derivados , Floroglucinol/isolamento & purificação , Xantonas/isolamento & purificação , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Humanos , Estrutura Molecular , Floroglucinol/química , Floroglucinol/farmacologia , Folhas de Planta/química , Prenilação , Xantenos/química , Xantenos/farmacologia , Xantonas/química , Xantonas/farmacologia
20.
Phytomedicine ; 102: 154142, 2022 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-35623158

RESUMO

BACKGROUND: Pyroptosis, an inflammatory form of programmed cell death (PCD), is reported to play important roles in the treatment of tumors. In our previous studies, we found that neobractatin (NBT), a caged prenylxanthone isolated from edible fruits of Garcinia bracteata C. Y. Wu ex Y. H. Li, showed anticancer effects against different cancer cells. However, the effect of NBT on pyroptosis is not well understood. PURPOSE: This study aims to investigate whether and how GSDME-mediated pyroptosis contributes to NBT-induced antitumor effects in esophageal cancer (EC) cells. METHODS: Cell viability assay and colony formation assay were used to determine the anticancer effects of NBT in esophageal cancer cells. Lactate dehydrogenase (LDH) release assay and microscopy imaging were used to detect the main characteristic of pyroptosis. CRISPR-Cas9 knockout and siRNA knockdown were performed to verify the roles of GSDME and caspase-3 in NBT-induced pyroptosis. Flow cytometry was used to measure the reactive oxygen species (ROS) level and cell apoptosis. The changes of related protein level were detected by Western blot. Furthermore, animal experiments were used to verify the in vivo effect of NBT. RESULTS: The results showed that NBT reduced the viability of EC cells mainly through GSDME-mediated pyroptosis. Morphologically, NBT induced cell swelling and formed large bubbles emerging from plasma membrane in wild type EC cells. Furthermore, NBT induced the cleavage of GSDME by activating caspase-3 in EC cells. On the other hand, caspase-3 activated by NBT also induced apoptosis especially at high dosage. Knocking down GSDME switched NBT-induced cell death from mainly pyroptosis to apoptosis in vivo and in vitro. Mechanistic studies indicated that NBT led to accumulation of ROS, which then regulated the phosphorylation of both JNK and MEK/ERK. In the absence of ROS or caspase-3, NBT-induced pyroptosis and apoptosis were completely reversed. Moreover, NBT showed a significant antitumor effect in both the KYSE150 and GSDME knockout KYSE150-/- xenograft models by inducing pyroptosis and apoptosis, respectively. CONCLUSION: Our results indicated that natural compound NBT could induce GSDME-mediated pyroptosis and apoptosis in esophageal cancer cells, making it a potential therapeutic drug in clinical treatment.


Assuntos
Neoplasias Esofágicas , Garcinia , Animais , Caspase 3/metabolismo , Neoplasias Esofágicas/tratamento farmacológico , Humanos , Piroptose , Espécies Reativas de Oxigênio/metabolismo , Receptores de Estrogênio/metabolismo
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