RESUMO
Hepatocellular carcinoma has been known as the most frequent subtype of liver cancer with a high rate of spread, metastases, and recurrence, also dismal treatment effects. However, effective therapies for HCC are still required. Nowadays, natural products have been known as a valuable source for drug discovery. In this research, 44 sesquiterpene lactones isolated from the Elephantopus scaber Linn. (Asteraceae) were tested by MTT assay for the antitumor activities. Deoxyelephantopin (DET) was found to exert significant cytotoxicity on HepG2 and Hep3B cells. Moreover, we found that DET treatment markedly reduced the growth of HCC cells in a concentration-dependent manner, which was better than sorafenib. Furthermore, DET induced mitochondrial dysfunction, oxidative stress, and cellular apoptosis. Additionally, we found that DET and sorafenib synergistically induced apoptosis and mitochondrial dysfunction in HCC cells. DET combined with sorafenib was also efficacious in tumor xenograft model. Molecular docking experiments revealed that DET had a potentially high binding affinity with Hsp90α. Moreover, Drug Affinity Responsive Target Stability assay suggested that DET could directly target Hsp90α. Additionally, the expression of Hsp90α was both decreased in vitro and in vivo. Altogether, this study revealed that DET might be a promising agent for HCC therapy by targeting Hsp90α.
Assuntos
Asteraceae , Carcinoma Hepatocelular , Neoplasias Hepáticas , Sesquiterpenos , Humanos , Sesquiterpenos de Germacrano/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Sorafenibe/farmacologia , Simulação de Acoplamento Molecular , Neoplasias Hepáticas/tratamento farmacológico , Apoptose , Lactonas/farmacologia , Lactonas/química , Sesquiterpenos/farmacologia , Sesquiterpenos/química , Mitocôndrias , Asteraceae/química , Linhagem Celular TumoralRESUMO
Small molecule accurate recognition technology (SMART) is an emerging method for the rapid structural prediction of major constituents from crude extracts and fractions. In the present study, a targeted isolation of an Elephantopus scaber extract by SMART resulted in the obtention of 15 new (1-15) and five known germacranolide sesquiterpenes (16-20). Their structures were assigned by extensively analyzing HRESIMS, NMR, X-ray crystallographic analyses, modified Mosher's method results, and quantum chemical calculate electronic circular dichroism (ECD) spectra. All germacranolide sesquiterpenes were screened to determine their inhibitory effects with two hepatoma cell lines (HepG2 and Hep3B), and compounds 14, 16, 18, 19 and 20 showed significant cytotoxic activities against the HepG2 (IC50, 3.3-9.9 µM) and Hep3B (IC50, 4.5-8.6 µM) cell lines. Further study suggested that 18 can induce the apoptosis of hepatoma cells via mitochondrial dysfunction.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Asteraceae/química , Extratos Vegetais/farmacologia , Sesquiterpenos de Germacrano/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Sesquiterpenos de Germacrano/química , Sesquiterpenos de Germacrano/isolamento & purificação , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/isolamento & purificação , Relação Estrutura-AtividadeRESUMO
Chromatographic purification of Elephantopus scaber led to 16 new germacrane-type sesquiterpene lactones (1-16), named elephantopinolide A-P, along with a known analogue (17). Their structures were confirmed by comprehensive spectroscopic analyses, single-crystal X-ray diffraction, and comparison between the experimental and calculated ECD spectra. Their hepatocellular inhibition activities against Hep3B and HepG2 cells were screened by MTT assay, and the structure-activity relationships were examined. The results revealed that 10 (IC50 value of 2.83 µM and 1.98 µM) is more potent than sorafenib. The underlying mechanism study demonstrated that 10 could markedly induce apoptosis accompanied by increased ROS production and decreased mitochondrial membrane potential, resulting in the autophagy and G2/M phase cell arrest in Hep3B and HepG2 cells. Furthermore, signal pathways including MAPKs and AKT may play important roles in 10-induced hepatocellular carcinoma cells death.
Assuntos
Antineoplásicos/síntese química , Carcinoma Hepatocelular/tratamento farmacológico , Lactonas/química , Neoplasias Hepáticas/tratamento farmacológico , Magnoliopsida/química , Extratos Vegetais/síntese química , Sesquiterpenos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Fase G2 , Humanos , Sistema de Sinalização das MAP Quinases , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Modelos Moleculares , Extratos Vegetais/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sesquiterpenos de Germacrano/química , Relação Estrutura-AtividadeRESUMO
Seven undescribed terpenylated coumarins, named altissimacoumarin I-O, together with seven known compounds, altissimacoumarin C, altissimacoumarin E, altissimacoumarin G, altissimacoumarin H, puberulin, 7-(3-Methyl-2-butenyloxy)-6-methoxycoumarin and artelin were isolated from the root bark of Ailanthus altissima (Mill.) Swingle. Their structures were elucidated by comprehensive spectra data analysis, NMR calculation, DP4+ analysis and ACD/Structure Elucidator software simulation. The absolute configurations of altissimacoumarins K, L, M and N were determined by modified Mosher's method. All isolates were tested for their cytotoxic effect against two hepatoma carcinoma cell lines (HepG2, Hep3B). Altissimacoumarin C exhibited moderate cytotoxic effect against Hep3B cells, with IC50 of 45.21 µM.
Assuntos
Ailanthus , Cumarínicos , Casca de Planta , Extratos VegetaisRESUMO
Four pairs of ß-carboline enantiomers (1A: /1B: -4A: /4B: ), 2 ß-carboline derivatives (5: â-â6: ) with a single enantiomeric configuration, together with 2 known achiral congeners (7: â-â8: ) were isolated from the stems of Picrasma quassioides. Their structures were elucidated on the basis of extensive spectroscopic analyses and quantum mechanical calculations. Compound 5: possesses a 4,5-seco ß-carboline framework and represents the first example of this type of ß-carboline alkaloids from nature. A possible biosynthetic pathway is proposed to generate the racemate 4: and the enantiomerically pure compounds 5: and 6: . All isolates were screened for their cytotoxicity against hepatocellular carcinoma Hep3B and HepG2 cells, which revealed that enantiomeric compounds 4A: and 4B: had distinctive effects in HepG2 cells. Further investigation showed that 4B: could induce apoptosis in HepG2 cells.
Assuntos
Alcaloides/isolamento & purificação , Antineoplásicos Fitogênicos/isolamento & purificação , Carbolinas/isolamento & purificação , Medicamentos de Ervas Chinesas/farmacologia , Picrasma/química , Alcaloides/química , Alcaloides/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Carbolinas/química , Carbolinas/farmacologia , Cromatografia , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Estrutura Molecular , EstereoisomerismoRESUMO
Timosaponin AIII, a major steroidal saponin found in Anemarrhena asphodeloides Bge., which has been widely used as anti-pyretic, anti-diabetic, anti-inflammatory, anti-platelet aggregator and anti-depressant agents in traditional Chinese medicine. Recent pharmacological study showed that timosaponin AIII had potent cytotoxicity, which was potential to be developed as an anticancer agent, however the molecular mechanism underlying the anticancer activity has not been fully elucidated. This review aims to give a systematic summary of the study of timosaponin AIII to reveal its anti-tumor activities by investigating invasion and migration, apoptosis, autophagy and reversing multi-drug resistance. Furthermore, we also make an overview of the mechanisms identified till now. These meaningful findings may provide novel insights on exploiting timosaponin AIII as a new anti-tumor agent.
Assuntos
Anemarrhena/química , Antineoplásicos/farmacologia , Saponinas/farmacologia , Esteroides/farmacologia , Antineoplásicos/isolamento & purificação , Antineoplásicos/uso terapêutico , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Humanos , Invasividade Neoplásica , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Saponinas/isolamento & purificação , Saponinas/uso terapêutico , Esteroides/isolamento & purificação , Esteroides/uso terapêuticoRESUMO
Four pairs of racemic phenylpropanoids (1a/1b-4a/4b), including five new compounds (1a/1b, 2a, 3a, and 4a) were obtained from the root barks of Ailanthus altissima (Mill.) Swingle. Their structures were determined by comprehensive spectroscopic analyses. The absolute configurations of the enantiomers were determined by comparison of the experimental ECD and OR with the calculated data. The antitumor activity of all isolates was evaluated against two human hepatoma carcinoma cells (HepG2 and Hep3B) in vitro. It was demonstrated that 1a/1b showed potent selective cytotoxicity against HepG2 cells. Additionally, 1a/1b could also induce apoptosis enantioselectively as demonstrated by Hoechst staining experiment.