RESUMO
Three pentacyclic triterpene dilactones were isolated from the fruiting bodies of Ganoderma colossum, a medicinal mushroom. Colossolactone H (colo H) as a new compound and the most cytotoxic among the isolates was studied for its anticancer mechanism and the potential use in cancer therapy. Gene expression profiling analysis indicated that treatment of lung cancer cells with colo H caused upregulation of 252 genes and downregulation of 398 genes. Gene ontology enrichment analysis indicated that the downregulated genes were the most significantly enriched in cell cycle progression, and the upregulated genes were significantly enriched in metabolic process, cellular response to stimulus, and oxidation reduction. Accordingly, colo H was found to halt cell growth and induce cell apoptosis via the elevation of cellular reactive oxygen species to cause DNA damage and the increase of tumor suppressor p53 protein. These events facilitate additive cytotoxicity of colo H and gefitinib for gefitinib-resistant H1650 lung cancer cells. Furthermore, combination of colo H and gefitinib effectively inhibited the growth of tumor xenografts in athymic mice. In addition to the efficacy in adjunctive cancer therapy, we have also demonstrated the isolation of colo H from cultivated G. colossum. Thus it is feasible to use colo H or Ganoderma colossum for cancer therapy.
Assuntos
Antineoplásicos/farmacologia , Ganoderma/química , Quinazolinas/farmacocinética , Triterpenos/farmacologia , Animais , Antineoplásicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Dano ao DNA , Regulação para Baixo , Gefitinibe , Humanos , Neoplasias Pulmonares , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Espécies Reativas de Oxigênio/metabolismo , Triterpenos/isolamento & purificação , Proteína Supressora de Tumor p53/metabolismo , Regulação para Cima , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The stilbenoids, arachidin-1 (Ara-1), arachidin-3, isopentadienylresveratrol, and resveratrol, have been isolated from germinating peanut kernels and characterized as antioxidant and anti-inflammatory agents. Resveratrol possesses anticancer activity, and studies have indicated that it induces programmed cell death (PCD) in human leukemia HL-60 cells. In this study, the anticancer activity of these stilbenoids was determined in HL-60 cells. Ara-1 had the highest efficacy in inducing PCD in HL-60 cells, with an approximately 4-fold lower EC50 than resveratrol. Ara-1 treatment caused mitochondrial membrane damage, activation of caspases, and nuclear translocation of apoptosis-inducing factor, resulting in chromosome degradation and cell death. Therefore, Ara-1 induces PCD in HL-60 cells through caspase-dependent and caspase-independent pathways. Ara-1 demonstrates its efficacy as an anticancer agent by inducing caspase-independent cell death, which is an alternative death pathway of cancer cells with mutations in key apoptotic genes. These findings indicate the merits of screening other peanut stilbenoids for anticancer activity.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Arachis/química , Leucemia/fisiopatologia , Extratos Vegetais/farmacologia , Estilbenos/farmacologia , Células HL-60 , Humanos , Sementes/químicaRESUMO
Lanostanoid triterpenes isolated from Ganoderma amboinense were found to inhibit the growth of numerous cancer cell lines, and some of them inhibited the activities of topoisomerases I and IIalpha in vitro. Among the bioactive isolates, one of the most potent triterpene was identified to be 3 alpha-hydroxy-15 alpha-acetoxy-lanosta-7,9(11),24-trien-26-oic acid, ganoderic acid X (GAX). Treatment of human hepatoma HuH-7 cells with GAX caused immediate inhibition of DNA synthesis as well as activation of ERK and JNK mitogen-activated protein kinases, and cell apoptosis. Molecular events of apoptosis including degradation of chromosomal DNA, decrease in the level of Bcl-xL, the disruption of mitochondrial membrane, cytosolic release of cytochrome c and activation of caspase-3 were elucidated. The ability of GAX to inhibit topoisomerases and to sensitize the cancer cells toward apoptosis fulfills the feature of a potential anticancer drug.
Assuntos
Antineoplásicos , Apoptose/fisiologia , Proteínas de Ligação a DNA/antagonistas & inibidores , Lanosterol , Lanosterol/análogos & derivados , Lanosterol/metabolismo , Inibidores da Topoisomerase I , Inibidores da Topoisomerase II , Triterpenos , Triterpenos/metabolismo , Antígenos de Neoplasias/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Caspase 3 , Caspases/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , DNA Topoisomerases Tipo I/metabolismo , DNA Topoisomerases Tipo II/metabolismo , Proteínas de Ligação a DNA/metabolismo , Ativação Enzimática , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Ganoderma/química , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Lanosterol/química , Lanosterol/uso terapêutico , Medicina Tradicional Chinesa , Estrutura Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Triterpenos/química , Triterpenos/uso terapêuticoRESUMO
Natural antimutagens may prevent cancer and are therefore of great interest to oncologists and the public at large. Phytochemicals are potent antimutagen candidates. When the Ames test was applied to examine the antimutagenic potency of supercritical carbon dioxide (SC-CO(2)) extracts of Terminalia catappa leaves at a dose of 0.5 mg/plate, toxicity and mutagenicity were not detected. The antimutagenic activity of SC-CO(2) extracts increased with decreases of temperature (60, 50, and 40 degrees C) and pressure (4000, 3000, and 2000 psi) used for extraction. The most potent antimutagenicity was observed in extracts obtained at 40 degrees C and 2000 psi. At a dose of 0.5 mg of extract/plate, approximately 80% of the mutagenicity of benzo[a]pyrene (B[a]P, with S-9) and 46% of the mutagenicity of N-methyl-N '-nitroguanidine (MNNG, without S-9) were inhibited. Media supplemented with SC-CO(2) extracts at a range of 0-500 microg/mL were used to cultivate human hepatoma (Huh 7) and normal liver (Chang liver) cells. The viability of the cells was assayed by measuring cellular acid phosphatase activity. A dose-dependent growth inhibition of both types of cells was observed. The SC-CO(2) extracts were more cytotoxic to Huh 7 cells than to Chang liver cells. The observation that SC-CO(2) extracts of T. catappa leaves did not induce mutagenicity at the doses tested while exhibiting potent antimutagenicity and were more cytotoxic to human hepatoma cells than to normal liver cells is of merit and warrants further investigation.
Assuntos
Antimutagênicos/toxicidade , Extratos Vegetais/toxicidade , Folhas de Planta/química , Terminalia/química , Fosfatase Ácida/metabolismo , Dióxido de Carbono , Sobrevivência Celular/efeitos dos fármacos , Humanos , Testes de Mutagenicidade , Pressão , Temperatura , Células Tumorais Cultivadas/efeitos dos fármacosRESUMO
The medicinal mushroom Ganoderma lucidum (G. lucidum) has been used in the Orient for the prevention and treatment of various diseases including cancer. Except for the immune enhancing properties of its polysaccharide constituent, very little is known about the anticancer activity of another major constituent, triterpenes. In this report, we studied the anticancer mechanism of triterpene-enriched extracts from G. lucidum. The triterpene-enriched fraction, WEES-G6, was prepared from mycelia of G. lucidum by sequential hot water extraction, removal of ethanol-insoluble polysaccharides and then gel-filtration chromatography. We found that WEES-G6 inhibited growth of human hepatoma Huh-7 cells, but not Chang liver cells, a normal human liver cell line. Treatment with WEES-G6 caused a rapid decrease in the activity of cell growth regulative protein, PKC, and the activation of JNK and p38 MAP kinases. The changes in these molecules resulted in a prolonged G2 cell cycle phase and strong growth inhibition. None of these effects were seen in the normal liver cells. Our findings suggest that the triterpenes contained in G. lucidum are potential anticancer agents.
Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Fase G2/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Proteínas Quinases Ativadas por Mitógeno/biossíntese , Proteína Quinase C/metabolismo , Reishi , Carcinoma Hepatocelular/enzimologia , Fracionamento Químico , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Medicamentos de Ervas Chinesas/química , Neoplasias Hepáticas/enzimologia , Proteína Quinase C/antagonistas & inibidores , Reishi/química , Triterpenos/farmacologia , Células Tumorais Cultivadas/efeitos dos fármacos , Células Tumorais Cultivadas/enzimologia , Proteínas Quinases p38 Ativadas por MitógenoRESUMO
Two new antioxidative and cytotoxic compounds, 10'(Z),13'(E),15'(E)-heptadecatrienylhydroquinone (1) and 10'(Z),13'(E)-heptadecadienylhydroquinone (2), as well as the known 10'(Z)-heptadecenylhydroquinone (3), were isolated from an EtOH extract of the sap of Rhus succedanea. The structures were elucidated by spectral analyses. These compounds showed antioxidative and cytotoxic activities against five cancer cell lines.