Novel mTOR inhibitory activity of ciclopirox enhances parthenolide antileukemia activity.

Ciclopirox, an antifungal agent commonly used for the dermatologic treatment of mycoses, has been shown recently to have antitumor properties. Although the exact mechanism of ciclopirox is unclear, its antitumor activity has been attributed to iron chelation and inhibition of the translation initiation factor eIF5A. In this study, we identify a novel function of ciclopirox in the inhibition of mTOR. As with other mTOR inhibitors, we show that ciclopirox significantly enhances the ability of the established preclinical antileukemia compound, parthenolide, to target acute myeloid leukemia. The combination of parthenolide and ciclopirox demonstrates greater toxicity against acute myeloid leukemia than treatment with either compound alone. We also demonstrate that the ability of ciclopirox to inhibit mTOR is specific to ciclopirox because neither iron chelators nor other eIF5A inhibitors affect mTOR activity, even at high doses. We have thus identified a novel function of ciclopirox that might be important for its antileukemic activity.

Cholesterol sequestration by nystatin enhances the uptake and activity of endostatin in endothelium via regulating distinct endocytic pathways.

Specific internalization of endostatin into endothelial cells has been proved to be important for its biologic functions. However, the mechanism of endostatin internalization still remains elusive. In this study, we report for the first time that both caveolae/lipid rafts and clathrin-coated pits are involved in endostatin internalization. Inhibition of either the caveolae pathway or the clathrin pathway with the use of chemical inhibitors, small interfering RNAs, or dominant-negative mutants alters endostatin internalization in vitro. Intriguingly, cholesterol sequestration by nystatin, a polyene antifungal drug, significantly enhances endostatin uptake by endothelial cells through switching endostatin internalization predominantly to the clathrin-mediated pathway. Nystatin-enhanced internalization of endostatin also increases its inhibitory effects on endothelial cell tube formation and migration. More importantly, combined treatment with nystatin and endostatin selectively enhances endostatin uptake and biodistribution in tumor blood vessels and tumor tissues but not in normal tissues of tumor-bearing mice, ultimately resulting in elevated antiangiogenic and antitumor efficacies of endostatin in vivo. Taken together, our data show a novel mechanism of endostatin internalization and support the potential application of enhancing the uptake and therapeutic efficacy of endostatin via regulating distinct endocytic pathways with cholesterol-sequestering agents.

Atividade antifúngica dos óleos essenciais de sassafrás (Ocotea odorifera Vell. ) e alecrim (Rosmarinus officinalis L. ) sobre o gênero Candida / Antifungal activity of Brazilian sassafras (Ocotea odorifera Vell. ) and rosemary (Rosmarinus officinalis L. ) essential oils against the genus Candida

Este estudo objetivou avaliar, in vitro, a atividade antifúngica dos óleos essenciais de Ocotea odorifera (Vellozo) Rohwer (Sassafrás) e Rosmarinus officinalis L. (Alecrim) sobre cepas de Candida albicans e C. tropicalis, envolvidas com infecções da cavidade oral. Para tanto, 16 cepas de Candida de origem clínica e de referência foram utilizadas para determinação da concentração inibitória mínima (CIM), utilizando a técnica da microdiluição. Miconazol e nistatina foram utilizados como controles positivos. Observou-se discreta atividade antifúngica de ambos os óleos, com CIM de 2,5 mg mL-1 para sassafrás e CIM de 5 mg mL-1 para alecrim em 68 por cento e 81 por cento das cepas avaliadas, respectivamente. Todas as cepas de Candida mostraram-se sensíveis ao miconazol e nistatina. A partir dos resultados obtidos, foi possível concluir que os óleos essenciais de O. odorifera Vell. e R. officinalis L. apresentam fraca atividade sobre cepas de C. albicans e C. tropicalis envolvidas em infecções da cavidade oral.

This study aimed to evaluate the in vitro antifungal activity of essential oils from Ocotea odorifera Vell. (Brazilian sassafras) and Rosmarinus officinalis L. (rosemary) against Candida albicans and C. tropicalis strains, both involved in oral cavity infections. Thus, 16 Candida strains from clinical origin and standards were used to determine the minimum inhibitory concentration (MIC), using the microdilution technique. Miconazole and nystatin were used as positive controls. A slight antifungal activity was observed for both oils, with 2.5 mg mL-1 MIC for Brazilian sassafras and 5 mg mL-1 MIC for rosemary in 68 and 81 percent strains, respectively. All Candida strains were sensitive to miconazole and nystatin. In conclusion, essential oils from O. odorifera Vell. and R. officinalis L. had weak activity against C. albicans and C. tropicalis strains involved in oral cavity infections.

Efficacy of Origanum essential oils for inhibition of potentially pathogenic fungi / Eficácia de Origanum óleos essenciais para a inibição de fungos potencialmente patogênicos

This study aimed to assess the efficacy of O. vulgare L. and O. majorana L. essential oil in inhibiting the growth and survival of potentially pathogenic fungal strains and also sought to evaluate the possible mechanisms involved in the establishment of the antifungal property of the tested essential oils through assays of osmotic stability and morphogenesis. Test strains included in this study were Candida albicans ATCC 7645, C. tropicalis LM-14, C. krusei LM-09, Cryptococcus neoformans FGF-5, Aspergillus flavus LM-02, A. fumigatus IPP-21, T. rubrum ATCC 28184, T. mentagrophytes LM-64, Microsporum gypseum ATCC 184, M. canis LM-36 and Cladosporium herbarium ATCC 26362. O. vulgare essential oil presented a MIC value of 80 µL/mL, while for O. majorana this was 160 µL/mL. C. krusei LM-09 was the only strain resistant to all assayed concentrations of both essential oils. O. vulgare and O. majorana essential oil at their MIC values provided a cidal effect against C. albicans ATCC 7645 after 4 h of exposure. O. vulgare essential oil at 80 µL/mL exhibited 100 percent inhibition of the radial mycelia growth of T. rubrum ATCC 28184 and M. canis LM-36 for 14 days. Assayed fungus strain protected by sorbitol (osmo-protectant agent) grew in media containing higher concentrations of O. vulgare and O. majorana essential oil in comparison to media without sorbitol, suggesting some specificity of these essential oils for targeting cell wall in the fungi cell. Main morphological changes observed under light microscopy provided by the essential oil of O. vulgare in A. flavus LM-02 were decreased conidiation, leakage of cytoplasm, loss of pigmentation and disrupted cell structure indicating fungal wall degeneration. These results suggest that essential oils from Origanum could be regarded as a potential antifungal compound for controlling the growth of pathogen fungi and the occurrence of mycoses.

O objetivo deste estudo foi observar a eficácia do óleo essencial de O. vulgare L. e O. majorana L. na inibição do crescimento e sobrevivência de cepas de fungos potencialmente patogênicas, bem como avaliar os possíveis mecanismos envolvidos no estabelecimento da propriedade antifúngica dos óleos essenciais testados através do ensaio de estabilidade osmótica e morfogênese. As cepas fúngicas utilizadas neste estudo foram Candida albicans ATCC 7645, C. tropicalis LM-14, C. krusei LM-09, Cryptococcus neoformans FGF-5, Aspergillus flavus LM-02, A. fumigatus IPP-21, T. rubrum ATCC 28184, T. mentagrophytes LM-64, Microsporum gypseum ATCC 184, M. canis LM-36 e Cladosporium herbarium ATCC 26362. O óleo essencial de O. vulgare apresentou valor de CIM de 80 µL/mL, enquanto o óleo essencial de O. majorana apresentou valor de CIM de 160 µL/mL. C. krusei LM-09 apresentou-se como a única cepa resistente a todas as concentrações ensaiadas de ambos os óleos essenciais. Os óleos essenciais testados quando ensaiadas em seu valor de CIM causaram um efeito fungicida contra C. albicans ATCC 7645 após 4 h de exposição. O óleo essencial de O. vulgare na concentração de 80 µL/mL exibiu uma total inibição do crescimento micelial radial de T. rubrum ATCC 28184 e M. canis LM-36 ao longo de 14 dias. As cepas fúngicas ensaiadas quando tratadas com sorbitol (agente osmo-protetor) foram capazes de crescer em meio adicionado de mais altas concentrações dos óleos essenciais quando comparados ao meio não adicionado de sorbitol, sugerindo especificidade destes produtos a parede celular como alvo na célula fúngica. As principais alterações causadas pelo óleo essencial de O. vulgare sobre a morfologia de A. flavus LM-02 foram diminuída conidiação, perda de citoplasma, perda de pigmentação e ruptura da estrutura celular indicando degeneração da parede celular fúngica. Estes resultados sugerem que óleos essenciais de espécies de Origanum poderiam ser considerados como potenciais antifúngicos para ...