RESUMO
Acute myeloid leukemia (AML) is a hematologic malignancy associated with high morbidity and mortality. Here we describe a case of a patient with AML who presented a partial response after utilization of the non-steroidal anti-inflammatory drug nimesulide. The response was characterized by complete clearance of peripheral blood blasts and an 82% decrease of bone marrow blasts associated with myeloblast differentiation. We have then shown that nimesulide induces in vitro cell death and cell cycle arrest in all AML cell lines (HL-60, THP-1, OCI-AML2, and OCI-AML3). Weighted Correlation Network Analysis (WGCNA) of serial whole-transcriptome data of cell lines treated with nimesulide revealed that the sets of genes upregulated after treatment with nimesulide were enriched for genes associated with autophagy and apoptosis, and on the other hand, the sets of downregulated genes were associated with cell cycle and RNA splicing. Serial transcriptome of bone marrow patient sample confirmed the upregulation of genes associated with autophagy after the response to nimesulide. Lastly, we demonstrated that nimesulide potentiates the cytotoxic in vitro effect of several Food and Drug Administration (FDA)-approved chemotherapy drugs used in AML, including cytarabine.
RESUMO
OBJECTIVES: Dendritic cells (DCs) are antigen-presenting cells, essential for recognition and presentation of pathogens to T cells. Propolis, a resinous material produced by bees from various plants, exhibits numerous biological properties, highlighting its immunomodulatory action. Here, we assayed the effects of propolis on the maturation and function of human DCs. METHODS: DCs were generated from human monocytes and incubated with propolis and LPS. NF-κB and cytokines production were determined by ELISA. microRNA's expression was analysed by RT-qPCR and cell markers detection by flow cytometry. Colony-forming units were obtained to assess the bactericidal activity of propolis-treated DCs. KEY FINDINGS: Propolis activated DCs in the presence of LPS, inducing NF-kB, TNF-α, IL-6 and IL-10 production. The inhibition of hsa-miR-148a and hsa-miR-148b abolished the inhibitory effects on HLA-DR and pro-inflammatory cytokines. The increased expression of hsa-miR-155 may be correlated to the increase in TLR-4 and CD86 expression, maintaining LPS-induced expression of HLA-DR and CD40. Such parameters may be involved in the increased bactericidal activity of DCs against Streptococcus mutans. CONCLUSION: Propolis modulated the maturation and function of DCs and may be useful in the initial steps of the immune response, providing a novel approach to the development of DC-based strategies and for the discovery of new immunomodulators.
Assuntos
Antibacterianos/farmacologia , Anti-Inflamatórios/farmacologia , Citocinas/metabolismo , Células Dendríticas/efeitos dos fármacos , MicroRNAs/metabolismo , NF-kappa B/metabolismo , Própole/farmacologia , Streptococcus mutans/patogenicidade , Receptor 4 Toll-Like/metabolismo , Antígeno B7-2/metabolismo , Antígenos CD40/metabolismo , Células Cultivadas , Citocinas/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Células Dendríticas/microbiologia , Relação Dose-Resposta a Droga , Antígenos HLA-DR/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Interleucina-10/metabolismo , Interleucina-6/metabolismo , MicroRNAs/genética , NF-kappa B/imunologia , Transdução de Sinais/efeitos dos fármacos , Streptococcus mutans/imunologia , Receptor 4 Toll-Like/imunologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
OBJECTIVES: Propolis has been used in folk medicine in different regions of the world including Latin America. Propolis is a resinous mixture of substances collected by honey bees from several botanical sources, and its composition contains a rich chemical variety, depending on the geographical area and plant sources. Our aim was to compare the modulatory effect of propolis samples from three different countries of Latin America (Brazil, Cuba and Mexico) on pro- and anti-inflammatory cytokine production (tumor necrosis factor (TNF)-α and interleukin (IL)-10, respectively) by human monocytes. METHODS: Cells were incubated with propolis for 18 h at 37°C. Cell viability was assessed by 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide method, and cytokine production was determined by ELISA. KEY FINDINGS: All samples did not affect monocyte viability. Brazilian propolis stimulated both TNF-α and IL-10 production by monocytes. Cuban propolis stimulated TNF-α and inhibited IL-10 production, while Mexican sample exerted the opposite effect, inhibiting TNF-α and stimulating IL-10 production. The major compounds found in Brazilian, Cuban and Mexican propolis samples were artepillin C, isoflavonoids and pinocembrin, respectively. CONCLUSION: Brazilian, Cuban and Mexican propolis contained different components that may exert pro- and anti-inflammatory activity depending on concentration, what may provide a novel approach to the development of immunomodulatory drugs containing propolis.