RESUMO
During the search for signal transducer and activator of transcription 3 (STAT3) inhibitors from natural products, methyllucidone, isolated from Lindera species (Lauraceae), was identified as a STAT3 inhibitor. Methyllucidone inhibited STAT3 phosphorylation at tyrosine 705 in a dose- and time dependent manner in DU145 prostate cancer cells and suppressed IL-6-induced STAT3 phosphorylation at Tyr-705 in LNCaP cells. Methyllucidone decreased the expression levels of STAT3 target genes, such as cyclin D1, cyclin A, Bcl-2, Mcl-1, and survivin. Methyllucidone inhibited DU145 cell growth and induced apoptosis by arresting the cell cycle at G1 phase. Notably, knockdown of the MEG2 gene by small interfering RNA suppressed the ability of methyllucidone to inhibit STAT3 activation. Methyllucidone regulates STAT3 activity by modulating MEG2 expression, and our results suggest that this compound is a novel inhibitor of the STAT3 pathway and may be a useful lead molecule for the development of a therapeutic STAT3 inhibitor.
Assuntos
Ciclopentanos/farmacologia , Neoplasias da Próstata/genética , Proteínas Tirosina Fosfatases não Receptoras/genética , Fator de Transcrição STAT3/antagonistas & inibidores , Ciclopentanos/química , Ciclopentanos/isolamento & purificação , Relação Dose-Resposta a Droga , Humanos , Lauraceae/química , Masculino , Estrutura Molecular , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Proteínas Tirosina Fosfatases não Receptoras/metabolismo , Fator de Transcrição STAT3/metabolismo , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
To generate a biobetter that has improved therapeutic activity, we constructed scFv libraries via random mutagenesis of several residues of CDR-H3 and -L3 of hu4D5. The scFv clones were isolated from the phage display libraries by stringent panning, and their anti-proliferative activity against HER2-positive cancer cells was evaluated as a primary selection criterion. Consequently, we selected AH06 as a biobetter antibody that had a 7.2-fold increase in anti-proliferative activity (IC50: 0.81 nM) against the gastric cancer cell line NCI-N87 and a 7.4-fold increase in binding affinity (KD: 60 pM) to HER2 compared to hu4D5. The binding energy calculation and molecular modeling suggest that the substitution of residues of CDR-H3 to W98, F100c, A101 and L102 could stabilize binding of the antibody to HER2 and there could be direct hydrophobic interactions between the aromatic ring of W98 and the aliphatic group of I613 within HER2 domain IV as well as the heavy and light chain hydrophobic interactions by residues F100c, A101 and L102 of CDR-H3. Therefore, we speculate that two such interactions were exerted by the residues W98 and F100c. A101 and L102 may have a synergistic effect on the increase in the binding affinity to HER2. AH06 specifically binds to domain IV of HER2, and it decreased the phosphorylation level of HER2 and AKT. Above all, it highly increased the overall level of p27 compared to hu4D5 in the gastric cancer cell line NCI-N82, suggesting that AH06 could potentially be a more efficient therapeutic agent than hu4D5.
Assuntos
Regiões Determinantes de Complementaridade/genética , Receptor ErbB-2/metabolismo , Anticorpos de Cadeia Única/metabolismo , Anticorpos de Cadeia Única/farmacologia , Afinidade de Anticorpos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Modelos Moleculares , Biblioteca de Peptídeos , Fosforilação/efeitos dos fármacos , Anticorpos de Cadeia Única/genéticaRESUMO
Schwannoma is an encapsulated nerve sheath tumor that is distinct from neurofibromatosis. It is defined as the occurrence of multiple schwannomas without any bilateral vestibular schwannomas. A 46-year-old man with multiple schwannomas involving peripheral nerves of the ipsilateral lower extremity presented with neurologic symptoms. Electrodiagnostic studies revealed multiple mononeuropathies involving the left sciatic, common peroneal, tibial, femoral and superior gluteal nerves. Histologic findings confirmed the diagnosis of schwannoma. We reported this rare case of segmental schwannomatosis that presented with neurologic symptoms including motor weakness, which was confirmed as multiple mononeuropathies by electrodiagnostic studies.
Assuntos
Adenina/análogos & derivados , Antivirais/efeitos adversos , Fraturas Espontâneas/induzido quimicamente , Dor Lombar/etiologia , Organofosfonatos/efeitos adversos , Osteomalacia/induzido quimicamente , Osteomalacia/complicações , Sacro/lesões , Adenina/efeitos adversos , Adulto , Nádegas , Fraturas Espontâneas/fisiopatologia , Marcha , Humanos , Hipofosfatemia/induzido quimicamente , Imageamento por Ressonância Magnética , Masculino , Costelas/lesõesRESUMO
The methanolic extract of the leaves of Liriodendron tulipifera was found to show inhibitory activity towards farnesyl protein transferase (FPTase). Bioassay-guided fractionation of the methanolic extract resulted in the isolation of lipiferolide, an inhibitor of FPTase. This compound inhibited the FPTase activity in a dose-dependent manner, and showed cell growth inhibitory activity against several tumor cells.
Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Antineoplásicos Fitogênicos/farmacologia , Inibidores Enzimáticos/farmacologia , Liriodendron/química , Extratos Vegetais/farmacologia , Sesquiterpenos/farmacologia , Animais , Antineoplásicos Fitogênicos/isolamento & purificação , Bactérias/efeitos dos fármacos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/isolamento & purificação , Células HL-60 , Humanos , Células K562 , Leucemia L1210 , Espectroscopia de Ressonância Magnética , Camundongos , Sesquiterpenos/isolamento & purificaçãoRESUMO
Two biflavonoids, ginkgetin (1) and sciadopitysin (2), were isolated from the MeOH extract of the young branches of Taxus cuspidata, which inhibited phosphatase of regenerating liver-3 (PRL-3) with IC50 values of 25.8 and 46.2 microM, respectively. This is the first report on PRL-3 inhibitors, isolated from natural sources.
Assuntos
Biflavonoides/farmacologia , Flavonoides/farmacologia , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas Tirosina Fosfatases/antagonistas & inibidores , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Biflavonoides/química , Biflavonoides/isolamento & purificação , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/farmacologia , Flavonoides/química , Flavonoides/isolamento & purificação , Humanos , Estrutura Molecular , Proteínas de Neoplasias/metabolismo , Proteínas Tirosina Fosfatases/metabolismo , Taxus/químicaRESUMO
Four cyclopentenediones, farnesyl protein transferase inhibitors, and anti-tumor compounds were isolated from the methanolic extract of the fruits of Lindera erythrocarpa Makino (Lauraceae). The structure of the compounds was determined by spectral data including NMR and mass spectrometry, and cyclopentenediones such as methyllinderone (1), methyllucidone (2), lucidone (3), and linderone (4) were identified by comparing their reported spectral data with that of the literature values. Compounds 1-4 inhibited farnesyl protein transferase with IC50 value of 55.3+/-4.1, 42+/-1.9, 103+/-5.1, and 40+/-3.5 microM, respectively. Isolated compounds also inhibited the growth of various human cancer cell lines in a dose-dependent manner. Especially, Compounds 1 and 2 selectively inhibited the growth of H-ras-transformed rat-2 cell lines in comparison with normal rat-2 cells with a GI50 value of 0.3 and 0.85 microM, respectively. Methyllucidone strongly inhibited the growth of human cancer cells and colon tumor xenografted in nude mice. The anti-tumor effects of the compound were further confirmed with caspase-3 activation and degradation of PARP. The results suggest that methyllucidone can be a potential anti-cancer agent against H-ras-transformed tumor and will also be a good lead molecule for the development of anti-tumor drug.
Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Antineoplásicos/farmacologia , Ciclopentanos/farmacologia , Frutas/química , Lindera/química , Fitoterapia , Animais , Antineoplásicos/química , Apoptose , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclopentanos/química , Ciclopentanos/isolamento & purificação , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Camundongos , Camundongos Nus , RatosRESUMO
A new abietane, namely, 20-hydroxyferruginol (1), together with known ferruginol (2), 18-hydroxyferruginol (3), sugiol (4), and 6alpha-hydroxysugiol (5), were isolated from the cones of Sequoia sempervirens. Their structures were elucidated through spectral data. Compounds 1 and 5 strongly inhibited colon, lung, and breast human tumors and oncogene transformed cells with GI(50) 2-5 microg/mL.