In mature erythrocytes, glucose-6-phosphate dehydrogenase (G6PDH) and 6-phosphogluconate dehydrogenase (6PGDH) yield NADPH, a crucial cofactor of the enzyme glutathione reductase (GR) converting glutathione disulfide (GSSG) into its reduced state (GSH). GSH is essential for detoxification processes in and survival of erythrocytes. We explored whether the anti-inflammatory compounds Bay 11-7082, parthenolide and dimethyl fumarate (DMF) were able to completely deplete a common target (GSH), and to impair the function of upstream enzymes of GSH recycling and replenishment. Treatment of erythrocytes with Bay 11-7082, parthenolide or DMF led to concentration-dependent eryptosis resulting from complete depletion of GSH. GSH depletion was due to strong inhibition of G6PDH activity. Bay 11-7082 and DMF, but not parthenolide, were able to inhibit the GR activity. This approach "Inhibitors, Detection of their common target that is completely depleted or inactivated when pharmacologically relevant concentrations of each single inhibitor are applied, Subsequent functional analysis of upstream enzymes for this target" (IDS), can be applied to a broad range of inhibitors and cell types according to the selected target. The specific G6PDH inhibitory effect of these compounds may be exploited for the treatment of human diseases with high NADPH and GSH consumption rates, including malaria, trypanosomiasis, cancer or obesity.

• MeSH
• dimethyl fumarát farmakologie   MeSH
• eryptóza účinky léků   MeSH
• erytrocyty enzymologie   MeSH
• glukosa-6-fosfátdehydrogenasa * antagonisté a inhibitory   metabolismus   MeSH
• lidé MeSH
• nitrily farmakologie   MeSH
• seskviterpeny farmakologie   MeSH
• sulfony farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

B-chronic lymphocytic leukemia (B-CLL) is the most common form of leukemia in the western world. It results from a relentless accumulation of small mature monoclonal lymphocytes. Following a recent demonstration of a significant increase in the proliferative pool of CLL cells in vivo, the gradual accumulation of malignant B-CLL cells seems to be primarily the consequence of their selective survival advantages relative to their normal B-cell counterparts. As the disease is mainly caused by defective apoptosis it is thus a good candidate for treatment by proapoptotic agents. Even though a large amount of research has been done during the last past years, the prognosis has not changed. Because of this, new therapeutic strategies are urgently needed, especially those that could switch on new apoptotic responses. In order to test the ability of parthenolide, a sesquiterpene lactone, to induce apoptosis and cytotoxicity of B-CLL cells in vitro, we cultured these cells in the presence of this substance. Incubations were continued for 3 days. Samples of cells were taken from cultures at 0, 24, 48 and 72 hours to measure apoptosis and cell viability. Peripheral Blood Mononuclear Cells (PBMCs) from five normal donors were submitted to the same techniques and served as control samples. In this study we show for the first time that parthenolide has a potent apoptotic and cytotoxic effect on B-CLL. It is noteworthy that this substance has almost no impact on normal PBMCs. This evidence suggests that parthenolide might be a promising therapy for B-CLL.

• MeSH
• apoptóza účinky záření   MeSH
• B-lymfocyty patologie   účinky léků   MeSH
• cytotoxiny aplikace a dávkování   terapeutické užití   MeSH
• interpretace statistických dat MeSH
• lidé MeSH
• lymfoidní leukemie farmakoterapie   krev   MeSH
• seskviterpeny aplikace a dávkování   terapeutické užití   MeSH
• Check Tag
• lidé MeSH

We demonstrated that TNF-alpha suppressed differentiation and potentiated cell death induced by butyrate (NaBt) in both adenocarcinoma HT-29 and fetal FHC human colon cells in vitro. Since TNF-alpha is a typical activator of NF-kappaB pathway, we studied the role of NF-kappaB activation in cell differentiation and death during the TNF-alpha and NaBt co-treatment. TNF-alpha induced rapid NF-kappaB activation in both HT-29 and FHC cell lines and this effect was differently modulated by NaBt in these two cell lines. In HT-29 cells, NaBt potentiated NF-kappaB activity induced by TNF-alpha after 4h treatment. However, this initial potentiation of NF-kappaB activity was not observed in FHC cells. During additional time of TNF-alpha and NaBt co-treatment, NaBt decreased the TNF-alpha-mediated NF-kappaB activity in both cell types. We also detected a different response of HT-29 and FHC cells after the pre-treatment with the NF-kappaB inhibitor parthenolide. Our results indicated that NaBt-mediated differentiation and apoptosis of colon epithelial cells can be modulated by TNF-alpha. Furthermore, we found significant differences in the mechanism of the NaBt and TNF-alpha co-treatment effects between cells of non-cancer and cancer origin, suggesting that the NF-kappaB pathway may be more effectively involved in these processes in cancer cells.

• MeSH
• apoptóza účinky léků   MeSH
• buněčná diferenciace účinky léků   MeSH
• buněčné linie MeSH
• buněčný cyklus účinky léků   MeSH
• buňky HT-29 MeSH
• butyráty farmakologie   MeSH
• kolon cytologie   MeSH
• lékové interakce MeSH
• lidé MeSH
• NF-kappa B fyziologie   MeSH
• proliferace buněk účinky léků   MeSH
• TNF-alfa farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH

Nuclear factor-kappaB (NF-κB) upregulates the transcription of proteins that promote cell survival, stimulate growth, induce angiogenesis and reduce susceptibility to apoptosis. NF-κB signaling pathway is constitutively activated in myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), lymphomas and in multiple myeloma (MM). Inactive NF-κB is bound in the cytoplasm to its inhibitor IκB, which masks its nuclear localisation signal. Two protein kinases with a high degree of sequence similarity, IKKα and IKKβ, mediate phosphorylation of IκB proteins and represent a convergence point for most signal transduction pathways leading to NF-κB activation. The overexpression of NF-κB and its anti-apoptotic cytoprotective effect suggest that it might be a useful therapeutic target for the treatment of hematologic malignancies. Several drugs effective for the treatment of MM, including proteasome inhibitors, thalidomide, lenalidomide and arsenic trioxide, block NF-κB activation. New agents with NF-κB inhibitory activity enhance the anti-MM effects of conventional chemotherapeutic agents and reduce different side-effects. Triptolide (diterpenoid triepoxyde), a purified component of a traditional Chinese medicine, extracted from a shrub-like vine named Trypterygium wilfordii Hook F (TWHF) inhibits transcriptional activation of NF-κB and downregulates the expression of various NF-κB-regulated genes. Triptolide (10-80 ng/ml) induces apoptosis of MM cells and effectively inhibits cell growth of MM cells. NF-κB activation can be also inhibited by IKKβ-selective inhibitors, PS-1145dihydrochloride, MLN120B (both Millennium Pharmaceuticals, Cambridge, MA) and BMS-345541 (Bristol-Myers Squibb, Princeton, NJ). LC-1, the dimethylamino-parthenolide (DMAPT) derivative demonstrated significant cytotoxicity to AML blasts targeting NF-κB.

• MeSH
• diterpeny chemie   terapeutické užití   MeSH
• epoxidové sloučeniny chemie   terapeutické užití   MeSH
• etodolac chemie   terapeutické užití   MeSH
• fenantreny chemie   terapeutické užití   MeSH
• hematologické nádory farmakoterapie   MeSH
• inhibitory proteasomu MeSH
• lidé MeSH
• NF-kappa B antagonisté a inhibitory   genetika   metabolismus   MeSH
• proteasomový endopeptidasový komplex metabolismus   MeSH
• proteiny I-kappa B metabolismus   MeSH
• protinádorové látky chemie   terapeutické užití   MeSH
• protokoly protinádorové kombinované chemoterapie terapeutické užití   MeSH
• signální transdukce MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Parthenolid je farmakologicky účinná látka přirozeně se vyskytující v řimbabě (Pyrethrum/Tanacetum parthenium), která je v lidovém léčitelství využívána pro své protizánětlivé účinky. Jelikož jsou literárně popisovány i její antiproliferační účinky na některé typy nádorových buněk, v poslední době byla in vitro hodnocena její schopnost působit analogicky na králičí synoviocyty (HIG-82), lidské synoviocyty či kožní fibroblasty. Zatímco proliferační aktivita kožních fibroblastů zůstala prakticky neovlivněna, králičí i lidské synoviocyty byly inhibovány ve výrazně vyšší míře.