RESUMO
Seventeen acridone alkaloids isolated from the Rutaceous plants were tested for their inhibitory activities against Epstein-Barr virus early antigen activation induced by 12-O-tetradecanoylphorbol-13-acetate in Raji cells. Some prenylated acridones were found to have remarkably potent activities. 1,3-Dihydroxy-10-methyl-2,4-diprenylacridone (18) as synthesized according to these results in vitro, exhibited a marked inhibitory effect on mouse skin tumor promotion in an in vivo two-stage carcinogenesis test. The result of the present investigation indicated that some of these acridone alkaloids may be potentially valuable cancer chemopreventive agents.
Assuntos
Acridinas/farmacologia , Alcaloides/farmacologia , Anticarcinógenos/farmacologia , Herpesvirus Humano 4/genética , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/prevenção & controle , Acridonas , Animais , Bioensaio , Carcinógenos , Feminino , Herpesvirus Humano 4/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Modelos Químicos , Neoplasias Cutâneas/metabolismo , Acetato de Tetradecanoilforbol , Fatores de TempoRESUMO
In our joint project involving search of anti-tumor promoters from natural plant sources, six phenylpropanoids and seven phytoquinoids isolated from three Illicium plants (Illiciaceae) were tested for their inhibitory activities against Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate in Raji cells. All tested compounds showed inhibitory activity against the EBV-EA activation even at 1 x 10mol ratio, and the inhibitory activity of their compounds was found to be more than that of beta-carotene. Two phenylpropanoids having prenyl group, 4-allyl-2-methoxy-6-(3-methyl-2-butenyl)phenol (3) and 4-allyl-2,6-dimethoxy-3-(3-methyl-2-butenyl)phenol (4), showed more potent activities as anti-tumor promoters (IC50 224 and 217 mol ratio/TPA, respectively). The presence of a prenyl moiety in the phenylpropanoids plays an important role in anti-tumor promoting activity as xanthone, coumarin and flavonoid previously reported. This investigation indicated that prenylated phenylpropanoids might be valuable as potential cancer chemopreventive agents.
Assuntos
Hidroquinonas/farmacologia , Illicium/química , Linfoma/patologia , Propanóis/farmacologia , Antígenos Virais/análise , Quimioprevenção , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Extratos Vegetais/farmacologia , Células Tumorais CultivadasRESUMO
Ultraviolet light is the most common cause of skin cancers in humans and several effects of ultraviolet light B (UVB: 290-320 nm) are thought to contribute to skin photocarcinogenesis. The generation of free radicals and related oxidants produced by UVB exposure, result in photocarcinogenesis by directly damaging DNA. On the other side, activating of transcription factor, activator protein 1 (AP-1) induced by UVB exposure causes tumor promotion. alpha-tocopherol has two principal physiological activities and one is an antioxidant activity through which alpha-tocopherol protects unsaturated fatty acids, protein and DNA from oxidation. The other activity is to stabilize the structure of the biomembrane. In addition to these two activities, it has been recently established that alpha-tocopherol plays important roles in cell signal transduction. In course of these studies, we examined such effects of alpha-tocopherol on UVB induced skin photocarcinogenesis in hairless mice. These results indicate that oral feeding of alpha-tocopherol including diet exhibited a marked inhibitory effects on both tumor incidence and multiplicity in UVB induced mouse skin photocarcinogenesis.
Assuntos
Neoplasias Induzidas por Radiação/prevenção & controle , Neoplasias Cutâneas/prevenção & controle , Raios Ultravioleta/efeitos adversos , alfa-Tocoferol/farmacologia , Administração Oral , Animais , Feminino , Camundongos , Camundongos Pelados , alfa-Tocoferol/administração & dosagemRESUMO
Three new chalcones, xanthoangelol I (1), xanthoangelol J (2), and deoxydihydroxanthoangelol H (3), were isolated from an ethyl acetate-soluble fraction of exudates of the stems of Angelica keiskei, and their structures were established on the basis of spectroscopic methods. Nine aromatic compounds of known structure, 4-12, and a diacetylene, 13, were also isolated and identified from this same fraction. On evaluation of these compounds for their inhibitory effects on the induction of Epstein-Barr virus early antigen (EBV-EA) by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells, 1, 2, 4, and 9-12 showed potent inhibitory effects on EBV-EA induction. In addition, upon evaluation of the inhibitory effects against activation of (+/-)-(E)-methyl-2[(E)-hydroxyimino]-5-nitro-6-methoxy-3-hexemide (NOR 1), a nitrogen oxide (NO) donor, six compounds, namely, 1, 2, 4, 9, 11, and 12, exhibited potent inhibitory effects. Further, isobavachalcone (4) exhibited inhibitory effects on skin tumor promotion in an in vivo two-stage mouse skin carcinogenesis test using 7,12-dimethylbenz[a]anthracene (DMBA) as an initiator and TPA as a promoter.
Assuntos
Angelica/química , Anticarcinógenos/isolamento & purificação , Chalconas/isolamento & purificação , Plantas Medicinais/química , Anticarcinógenos/química , Anticarcinógenos/farmacologia , Antígenos Virais/biossíntese , Antígenos Virais/efeitos dos fármacos , Chalconas/química , Chalconas/farmacologia , Humanos , Indonésia , Estrutura MolecularRESUMO
In continuation of our previous report, cimigenol (1) and 15 related compounds were screened as potential antitumor promoters by using the in vitro short-term 12-O-tetradecanoylphorbol-13-acetate (TPA)--induced Epstein-Barr virus early antigen (EBV-EA) activation assay. Cimigenol-3,15-dione (2) displayed the greatest potency (100% inhibition at 1000 mol ratio/TPA) and consequently was further examined for antitumor-promoting activity in a two-stage carcinogenesis assay of mouse skin tumors (DMBA/TPA). In this assay, compound 2 showed significant activity, reducing the number of papillomas per mouse to 48% of the control group at 20 weeks. In addition, compounds 1 and 2 were examined for antitumor-initiating activity in a two-stage carcinogenesis assay of mouse skin tumors induced by peroxynitrite as an initiator and TPA as a promoter. Results showed that these two triterpenoids were almost equipotent with epigallocatechin gallate (EGCG) and slightly more potent than tocinol (group V), the positive controls. Thus, compounds 1 and 2 exhibited not only strong antitumor-promoting activity but also significant antitumor-initiating effect on mouse skin. These data suggest that both compounds might be valuable chemopreventors.
Assuntos
Anticarcinógenos/farmacologia , Lanosterol/análogos & derivados , Lanosterol/farmacologia , Animais , Anticarcinógenos/química , Feminino , Lanosterol/química , Camundongos , Camundongos Endogâmicos ICR , Papiloma/prevenção & controle , Neoplasias Cutâneas/prevenção & controleRESUMO
We describe the isolation and spectrometric structure elucidation of eight new xanthones, fuscaxanthone A (1), B (2), C (3), D (4), E (5), F (6), G (7), and H (8), together with eight known xanthones from the stem bark of Garcinia fusca collected in Thailand. All the new xanthones were shown to have a terpenoid (prenyl and/or geranyl) side chain(s) in their molecules. We also present the results of a primary screening of the inhibitory effects of eight xanthones (9-16) isolated as major components of this plant on 12-O-tetradecanoylphorbol-13-acetate induced Epstein-Barr virus early antigen activation in Raji cells.
Assuntos
Garcinia/química , Plantas Medicinais/química , Xantenos/isolamento & purificação , Antígenos Virais , Estrutura Molecular , Relação Estrutura-Atividade , Tailândia , Xantenos/química , Xantenos/farmacologiaRESUMO
Continuing our search for cancer chemopreventive agents from natural sources, we examined constituents of the stem bark of Calophyllum brasiliense. Three new 4-substituted coumarins named brasimarins A (2), B (3), and C (4) were isolated and characterized, along with 11 known coumarins belonging to the calanolides or inophyllums. We also discuss the inhibitory effects of these coumarins on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells.
Assuntos
Anticarcinógenos/isolamento & purificação , Calophyllum/química , Cumarínicos/isolamento & purificação , Plantas Medicinais/química , Anticarcinógenos/química , Anticarcinógenos/farmacologia , Antígenos Virais/efeitos dos fármacos , Brasil , Células Cultivadas/efeitos dos fármacos , Cumarínicos/química , Cumarínicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Linfoma de Células B , Ressonância Magnética Nuclear Biomolecular , Casca de Planta/química , Acetato de Tetradecanoilforbol/farmacologiaRESUMO
The structure of a triterpenoid isolated from the nonsaponifiable lipid (NSL) of the seed oil of the camellia (Camellia japonica L.; Theaceae) was established to be (20S)-3beta-hydroxy-25,26,27-trisnordammaran-24,20-olide (1; 3-epicabraleahydroxylactone) on the basis of spectroscopic and chemical methods. Six other triterpenoids isolated from the NSL were identified as 3-epicabraleadiol (2), ocotillol II (3), ocotillol I (4), dammarenediol II (5), (20R)-taraxastane-3beta,20-diol (6), and lupane-3beta,20-diol (7). Upon evaluation of the seven triterpenoids (1-7) with respect to their inhibitory effects on the induction of Epstein-Barr virus early antigen (EBV-EA) by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells, three compounds (5-7) showed potent inhibitory effects against EBV-EA induction (IC(50) values of 277-420 mol ratio/32 pmol TPA).
Assuntos
Antivirais/química , Antivirais/farmacologia , Camellia/química , Herpesvirus Humano 4/efeitos dos fármacos , Lactonas/química , Lactonas/farmacologia , Óleos de Plantas/química , Óleos de Plantas/farmacologia , Triterpenos/química , Triterpenos/farmacologia , Antígenos Virais/metabolismo , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Humanos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Acetato de Tetradecanoilforbol/farmacologiaRESUMO
After bioassay-guided fractionation of the extract from Sandoricum koetjape bark, which exhibited significant toxicity to killifish (Oryzias latipes), two ichthyotoxic triterpenoids were isolated and characterized as koetjapic acid and 3-oxo-olean-12-en-29-oic acid. These constituents, along with non-toxic katonic acid, had a remarkable inhibitory effect on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol 13-acetate (TPA), which is a preliminary in vitro screening method for possible anti-tumor-promoting agents. Of the triterpenoids active in vitro, koetjapic acid appears to be a promising cancer chemopreventive agent, since it significantly delayed tumor promotion in two-stage mouse skin carcinogenesis induced by 7,12-dimethylbenz(a)anthracene and promoted by TPA.
Assuntos
Anticarcinógenos , Fundulidae/fisiologia , Meliaceae/química , Triterpenos/farmacologia , Triterpenos/toxicidade , 9,10-Dimetil-1,2-benzantraceno/antagonistas & inibidores , 9,10-Dimetil-1,2-benzantraceno/toxicidade , Animais , Carcinógenos/antagonistas & inibidores , Carcinógenos/toxicidade , Antígenos Nucleares do Vírus Epstein-Barr/efeitos dos fármacos , Feminino , Camundongos , Camundongos Endogâmicos ICR , Casca de Planta/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Acetato de Tetradecanoilforbol/antagonistas & inibidores , Acetato de Tetradecanoilforbol/toxicidade , Triterpenos/isolamento & purificaçãoRESUMO
Imatinib mesylate, a competitive inhibitor of Abl tyrosine kinase, is highly effective for the early stages of chronic myelogenous leukemia (CML), but remissions induced in advanced-phase CML and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia tend to be relatively short-lived. Therefore, the search for agents that enhance the anti-Ph+ effect of imatinib mesylate is warranted. We investigated the combined effects of imatinib mesylate and the third-generation bisphosphonate zoledronate (ZOL) on Ph+ leukemias, because ZOL inhibited the prenylation of Ras-related proteins downstream of Bcr/Abl. First, we identified the potency of ZOL in vitro against human leukemic cell lines, including 2 Ph+ and a P-glycoprotein-overexpressing leukemic cell line. ZOL was also effective in vivo because as it prolonged the survival of nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice who were given xenografts with Ph+ BV173 leukemic cells. Next, we showed the in vitro synergistic effects with ZOL and imatinib mesylate for Ph+ cell lines. ZOL combined with imatinib mesylate showed synergistic effects in vivo that prolonged the survival of mice inoculated with BV173. ZOL only minimally inhibited the growth of normal hematopoietic progenitors in vitro, and mice receiving ZOL or imatinib mesylate or both tolerated these treatments well. These findings indicate that ZOL is a potent antileukemic agent that augments synergistically the anti-Ph+ leukemia activity of imatinib mesylate.
Assuntos
Antineoplásicos/farmacologia , Difosfonatos/farmacologia , Imidazóis/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Piperazinas/farmacologia , Pirimidinas/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Apoptose/efeitos dos fármacos , Benzamidas , Divisão Celular/efeitos dos fármacos , Difosfonatos/toxicidade , Sinergismo Farmacológico , Células HL-60 , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Humanos , Mesilato de Imatinib , Imidazóis/toxicidade , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Pamidronato , Prenilação de Proteína , Ácido ZoledrônicoRESUMO
The structures of three triterpene alcohols isolated from the latex of Euphorbia antiquorum were established to be eupha-7,9(11),24-trien-3beta-ol (2; antiquol C), 19(10-->9)abeo-8alpha,9beta,10alpha-eupha-5,24-dien-3beta-ol (3; antiquol B), and 24-methyltirucalla-8,24(24(1))-dien-3beta-ol (4; euphorbol) on the basis of spectroscopic methods. Compounds 3 and 4 have previously been assigned the erroneous structures of 10alpha-cucurbita-5,24-dien-3alpha-ol and 24-methyleupha-8,24(24(1))-dien-3beta-ol, respectively. Compounds 2-4 and four other known compounds isolated from the latex, euphol (1), lemmaphylla-7,21-dien-3beta-ol (5), isohelianol (6), and camelliol C (7), showed potent inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA).