• Klíčová slova
• VENCLYXTO + rituximab,
• MeSH
• chinazoliny terapeutické užití   MeSH
• leukemie T-buněčná * farmakoterapie   patofyziologie   patologie   MeSH
• lidé MeSH
• protein BCL2L11 antagonisté a inhibitory   MeSH
• protokoly antitumorózní kombinované chemoterapie MeSH
• puriny terapeutické užití   MeSH
• reziduální nádor farmakoterapie   krev   MeSH
• rituximab terapeutické užití   MeSH
• sulfonamidy terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• klinické zkoušky, fáze III MeSH

UNLABELLED: 9-Norbornyl-6-chloropurine (NCP) is a representative of a series of antienteroviral bicycle derivatives with selective cytotoxicity towards leukemia cell lines. In this work we explored the mechanism of the antileukemic activity of NCP in T-cell lymphoblast cells (CCRF-CEM). Specifically, we searched for a potential link between its ability to induce cell death on the one hand and to modulate intracellular glutathione (GSH) that is necessary to its metabolic transformation via glutathione-S-transferase on the other hand. We have observed that GSH levels decreased rapidly in NCP-treated cells. Despite a complete regeneration following 24h of incubation with NCP, this profound drop in cellular GSH content triggered ER stress, ROS production and lipid peroxidation leading to the loss of mitochondrial membrane potential (MMP). These events induced concentration-dependent cell cycle arrest in G2/M phase and apoptosis. Both MMP loss and apoptosis were reversed by sulfhydryl-containing compounds (GSH, N-acetyl-l-cysteine). Furthermore, we have also shown that NCP-induced GSH decrease activated the Nrf2 pathway and its downstream targets NAD(P)H: quinone oxidoreductase (NQO-1) and glutamate cysteine ligase modifier subunit (GCLm), thus explaining the fast restoration of GSH pool and ROS decrease. Importantly, we confirmed that the cell death-inducing properties of the compounds were co-dependent on their ability to diminish cellular GSH level by analyzing the relationships between the GSH-depleting potency and cytotoxicity in a series of other norbornylpurine analogs. Altogether, the results demonstrated that in CCRF-CEM cells NCP triggered apoptosis through GSH depletion-associated oxidative and ER stress and mitochondrial depolarization.

• MeSH
• apoptóza účinky léků   MeSH
• glutamátcysteinligasa genetika   MeSH
• glutathion metabolismus   MeSH
• glutathiontransferasa genetika   MeSH
• leukemie T-buněčná farmakoterapie   genetika   metabolismus   patologie   MeSH
• lidé MeSH
• mitochondrie účinky léků   patologie   MeSH
• NAD(P)H dehydrogenasa (chinon) genetika   MeSH
• oxidační stres účinky léků   MeSH
• peroxidace lipidů účinky léků   MeSH
• puriny aplikace a dávkování   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• regulace genové exprese u leukemie účinky léků   MeSH
• stres endoplazmatického retikula účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

This work describes cytotoxic effect of non-platinum metal-based compounds on the human T-leukemic cells with different p53 status (p53 wild-type MOLT-4 and p53-deficient Jurkat cells). The cytotoxic and apoptosis-inducing effect of the vanadium complex [(η(5)-C5H5)2V(5-NH2-phen)]OTf (V1) and molybdenum complex [(η(3)-C3H5)Mo(CO)2(phen)Cl] (Mo1) were studied using flow cytometry, spectrophotometry and Western blotting. We found that the cytotoxic effect of both tested complexes after 24 h is higher against the both examined cell lines than that of cis-platin (cis-DDP). At later investigated time intervals of 48 and 72 h, the cytotoxic effect of the cis-DDP increased but the values of the cytotoxicity of the tested V1 and Mo1 complexes remained unchanged, with the cytotoxicity of V1 comparable to that of cis-DDP. Furthermore we observed that the apoptotic process was induced by the activation of the caspases 9 (intrinsic pathway) and 8 (extrinsic pathway) in cells exposed to evaluated complexes. In case of the p53 wild-type MOLT-4 cells, the expression of the tumor-suppressor protein p53 and its form phosphorylated at the serine 15 increased after both V1 and Mo1 treatment, similar to the effect of cis-DDP.

• MeSH
• antitumorózní látky farmakologie   MeSH
• apoptóza účinky léků   MeSH
• fosforylace účinky léků   MeSH
• kaspasy metabolismus   MeSH
• léky antitumorózní - screeningové testy MeSH
• leukemie T-buněčná farmakoterapie   metabolismus   patologie   MeSH
• lidé MeSH
• molybden chemie   farmakologie   MeSH
• nádorové buněčné linie MeSH
• nádorový supresorový protein p53 metabolismus   MeSH
• organokovové sloučeniny chemie   farmakologie   MeSH
• proliferace buněk účinky léků   MeSH
• serin metabolismus   MeSH
• vanad chemie   farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Present-day oncology sees at least two-thirds of cancer patients receiving radiation therapy as a part of their anticancer treatment. The objectives of the current study were to investigate the effects of the small molecule inhibitors of Wee1 kinase II (681641) and Rad51 (RI-1) on cell cycle progression, DNA double-strand breaks repair and apoptosis following ionizing radiation exposure in human leukemic T-cells Jurkat and MOLT-4. Pre-treatment with the Wee1 681641 or Rad51 RI-1 inhibitor alone increased the sensitivity of Jurkat cells to irradiation, however combining both inhibitors together resulted in a further enhancement of apoptosis. Jurkat cells pre-treated with inhibitors were positive for γH2AX foci 24h upon irradiation. MOLT-4 cells were less affected by inhibitors application prior to ionizing radiation exposure. Pre-treatment with Rad51 RI-1 had no effect on apoptosis induction; however Wee1 681641 increased ionizing radiation-induced cell death in MOLT-4 cells.

• MeSH
• inhibitory proteinkinas farmakologie   MeSH
• ionizující záření MeSH
• jaderné proteiny antagonisté a inhibitory   MeSH
• Jurkat buňky MeSH
• leukemie T-buněčná enzymologie   genetika   patologie   MeSH
• lidé MeSH
• oprava DNA MeSH
• poškození DNA účinky záření   MeSH
• proteiny buněčného cyklu antagonisté a inhibitory   MeSH
• rekombinasa Rad51 antagonisté a inhibitory   MeSH
• tyrosinkinasy antagonisté a inhibitory   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The effect of valproic acid (VA) on protein expression in human T-lymphocytic leukemia cells MOLT-4 was studied. VA is an inhibitor of histonedeacetylases and has a potential use as antitumor agent in leukemia treatment. The authors in this work prove that 4 h long incubation with 2 mmol/l VA causes phosphorylation of histone H2A.X and its colocalization with 53BP1 in nuclear foci. Their co-localization is typical for DSB signaling machinery. These foci were detected in cells after 4 h exposure without increase of Annexin V positive apoptotic cells. Slight increase in apoptosis (Annexin V positivity) after 24 h is accompanied by more intensive increase in phosphorylation of H2A.X and also by formation of nuclear foci containing gammaH2A.X and 53BP1. Treatment of cells with 2 mmol/l VA resulted in induction of apoptosis affecting about 30% of cells after incubation for 72 h. The changes in protein expression were examined after cell incubation with 2 mmol/l VA for 4 h. Proteins were separated by two-dimensional electrophoresis and quantified using image evaluation system. Those exhibiting significant VA-induced abundance alterations were identified by mass spectrometry. Changes in expression of 22 proteins were detected, of which 15 proteins were down-regulated. Proteomic analysis resulted in successful identification of three proteins involving alfa-tubulin 3, tubulin-specific chaperone and heterogeneous nuclear ribonucloprotein F. Expression of seven proteins was up-regulated, including heterogeneous nuclear ribonucloprotein A/B. Identified proteins are related to microtubular system and hnRNP family. Suppression of microtubular proteins and changes of balance among hnRNPs can contribute to proliferation arrest and apoptosis induction.

• MeSH
• 2D gelová elektroforéza MeSH
• annexin A5 metabolismus   MeSH
• apoptóza účinky léků   MeSH
• financování organizované MeSH
• heterogenní jaderné ribonukleoproteiny metabolismus   MeSH
• inhibitory enzymů farmakologie   MeSH
• kyselina valproová farmakologie   MeSH
• leukemie T-buněčná metabolismus   patologie   MeSH
• lidé MeSH
• nádorové proteiny metabolismus   MeSH
• proteom analýza   MeSH
• průtoková cytometrie MeSH
• signální transdukce MeSH
• spektrometrie hmotnostní - ionizace laserem za účasti matrice MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• srovnávací studie MeSH

Adenosine has been observed to suppress the growth of MOLT-4 human leukemia cells in vitro. Changes in the cell cycle, especially increased percentage of cells in S phase, prolonged generation time, and induction of apoptosis at higher adenosine concentrations have been found to be responsible for the growth suppression. Dipyridamole, a drug inhibiting the cellular uptake of adenosine, reversed partially but significantly the adenosine-induced growth suppression. It follows from these results that the action of adenosine on the MOLT-4 cells comprises its cellular uptake and intracellular operation. These findings present new data on anticancer efficacy of adenosine.

• MeSH
• adenosin antagonisté a inhibitory   farmakologie   metabolismus   MeSH
• antitumorózní látky antagonisté a inhibitory   farmakologie   metabolismus   MeSH
• apoptóza MeSH
• biologický transport účinky léků   MeSH
• dipyridamol farmakologie   MeSH
• financování organizované MeSH
• inhibitory fosfodiesteras farmakologie   MeSH
• leukemie T-buněčná patologie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• proliferace buněk účinky léků   MeSH
• Check Tag
• lidé MeSH

• MeSH
• CD antigeny genetika   MeSH
• dítě MeSH
• dospělí MeSH
• exprese genu MeSH
• imunofenotypizace MeSH
• leukemie T-buněčná etiologie   klasifikace   patologie   MeSH
• lidé MeSH
• nádorové biomarkery MeSH
• podskupiny lymfocytů genetika   imunologie   MeSH
• staging nádorů metody   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH

• MeSH
• interleukin-2 imunologie   terapeutické užití   MeSH
• krysa rodu rattus MeSH
• leukemie T-buněčná imunologie   patologie   terapie   MeSH
• rekombinantní proteiny MeSH
• transplantace nádorů MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH