- Klíčová slova
- venetoklax,
- MeSH
- antitumorózní látky terapeutické užití MeSH
- apoptóza účinky léků MeSH
- bicyklické sloučeniny heterocyklické terapeutické užití MeSH
- biomimetické materiály farmakologie MeSH
- lidé MeSH
- myelodysplastické syndromy * farmakoterapie MeSH
- protoonkogenní proteiny c-bcl-2 MeSH
- sulfonamidy terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
Závěrečná zpráva o řešení grantu Interní grantové agentury MZ ČR
Přeruš. str. : il., tab. ; 31 cm
Mantle cell lymphoma (MCL) is incurable B-cell non-Hodgkin lymphoma and thus improving an outcome of MCL patients with new treatment options is of great importance. We plan to evaluate impact of experimental combinatorial approaches on MCL cell lines both in vitro and in vivo (xenotransplants into immunodeficient mice) via targeting the MCL-associated aberrant molecular events by new generation of cytotoxic agents, e.g. roscovitine, gemcitabine or temsirolimus, and the death-receptor pathway by the proapoptotic cytokine TRAIL. We presuppose to identify novel TRAIL "sensitizers" among the new-generation anti-lymphoma drugs. We expect to elucidate yet undescribed molecular mechanisms, by which such sensitizers augment proapoptotic effects of the recombinant TRAIL. The results of this proposed project may have important implications for the therapy of mantle cell lymphoma and will provide substantiation for design of novel combinatorial approaches that may grant or prolong survival of MCL patients.
Lymfom z plášťových buněk (MCL) je nevyléčitelná forma B-nehodgkinského lymfomu (B-NHL). Vývoj a preklinické testování nových protilymfomových léků / léčebných strategií představuje proto zásadní prioritu. Cílem předkládaného projektu je vyhodnotit efektexperimentálních terapeutických postupů kombinujících cílený zásah do deregulovaných molekul / signálních drah nově zaváděnými protilymfomovými cytostatiky (např. bortezomib, temsirolimus, roscovitine) a indukci receptorové apoptotické dráhy proapoptotickým ligandem TRAILem. Experimenty budou prováděny in vitro na MCL buněčných liniích a in vivo na myším modelu lidského MCL (systémová xenotransplantace). Předpokládáme, že identifikujeme cytostatika, která budou vykazovat synergistický cytotoxický účinek s TRAILem. Očekáváme, že se nám podaří objasnit molekulární podstatu látkového synergismu. Výsledky studie mohou mít zásadní dopad na vytváření nových, klinicky účinnějších terapeutických postupů v léčbě lymfomu z plášťových buněk u člověka.
- MeSH
- apoptóza MeSH
- cytostatické látky MeSH
- experimentální terapie MeSH
- Jurkat buňky MeSH
- kaspasa 10 MeSH
- lymfom z plášťových buněk terapie MeSH
- modely u zvířat MeSH
- myši MeSH
- nehodgkinský lymfom terapie MeSH
- protein TRAIL MeSH
- synergismus léků MeSH
- transplantace heterologní MeSH
- Check Tag
- myši MeSH
- Konspekt
- Patologie. Klinická medicína
- NLK Obory
- hematologie a transfuzní lékařství
- onkologie
- NLK Publikační typ
- závěrečné zprávy o řešení grantu IGA MZ ČR
Apoptosis is a normal aspect of human physiology ensuring tissue homeostasis. Evasion of endogenous cell death processes, including apoptosis, represents one of the characteristics of cancer. Defects in the physiological mechanisms of apoptosis contribute to the pathological cell expansion and to the development and progression of cancer. Resistance of malignant cells to cancer therapeutic agents may be, in some cases, caused by dysregulation of apoptotic pathways, e.g. BCL2 or IAP overexpression. The understanding of the physiological mechanisms that control apoptosis and the elucidation of apoptotic defects in cancer cells may lead to the development of targeted cancer therapies. Apoptotic pathways, molecules involved in the cross-talk between individual apoptosis pathways and promising new anti-cancer agents, which trigger directly or indirectly apoptosis of hematologic cancer cells, are reviewed in this article.
- MeSH
- antitumorózní látky chemie terapeutické užití MeSH
- apoptóza účinky léků genetika MeSH
- chemorezistence MeSH
- epigeneze genetická účinky léků MeSH
- hematologické nádory farmakoterapie genetika metabolismus patologie MeSH
- lidé MeSH
- proteiny regulující apoptózu metabolismus MeSH
- racionální návrh léčiv MeSH
- regulace genové exprese u nádorů účinky léků MeSH
- signální transdukce účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
BACKGROUND: The fine balance in cellular life and death is affected by a number of tightly regulated, direct signals that can help to turn the balance either in favor of or against the ultimate fate. Among the most prominent players in the field of the extracellular signals leading to cell death, preferentially through induction of apoptosis belong several receptors from so-called Death Receptors group of the Tumour Necrosis Factors Receptors (TNFR) family. METHODS AND RESULTS: Over 15 years of the research on activation and regulation of the most prominent member of this group - receptors for the ligands TRAIL, FasL and TNFalpha brought not only a detail (and still refining) mechanism of these receptors activation and downstream signaling, but also connected them with the ultimate apoptotic gatekeeper - mitochondria. Mitochondria are, in addition to their essential role as the energy factories also repositories of a cavalry of apoptosis-inducing as well as regulatory proteins. However, in addition to the pro-death signaling, these receptors were also shown under certain circumstances to activate an opposite, pro-proliferative signaling as well as to participate in pro-inflammatory responses. CONCLUSIONS: Thus despite the concerned effort of a number of groups and thousands of published papers, novel roles for the intriguing group of these receptors and their ligands and fine tuning of their signaling still await to be uncovered. This cut-through review will be mainly focused on the prominent death-inducing members of this group - TNFR1, Fas/CD95 and TRAIL receptors.
- MeSH
- antigeny CD95 metabolismus MeSH
- financování organizované MeSH
- lidé MeSH
- receptory domény smrti metabolismus MeSH
- receptory TNF - typ I metabolismus MeSH
- receptory TNF metabolismus MeSH
- signální transdukce fyziologie MeSH
- TRAIL receptory metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- přehledy MeSH
Death receptor 6 (DR6/TNFRSF21) is a death domain-containing receptor of the TNFR superfamily with an apparent regulatory function in hematopoietic and neuronal cells. In this study we document that DR6 is an extensively posttranslationally modified transmembrane protein and that N- and O-glycosylations of amino acids in its extracellular part are mainly responsible for its approximately 40 kDa mobility shift in SDS polyacrylamide gels. Site-directed mutagenesis confirmed that all six extracellular asparagines are N-glycosylated and that the Ser/Thr/Pro cluster in the "stalk" domain juxtaposed to the cysteine-rich domains (CRDs) is a major site for the likely mucine-type of O-glycosylation. Deletion of the entire linker region between CRDs and the transmembrane domain, spanning over 130 amino acids, severely compromises the plasma membrane localization of DR6 and leads to its intracellular retention. Biosynthetic labeling with radiolabeled palmitate and side-directed mutagenesis also revealed that the membrane-proximal Cys368 in the intracellular part of DR6 is, similarly as cysteines in Fas/CD95 or DR4 ICPs, S-palmitoylated. However, palmitoylation of Cys368 is apparently not required for DR6 targeting into Brij-98 insoluble lipid rafts. In contrast, we show that N-glycosylation of the extracellular part might participate in directing DR6 into these membrane microdomains.
- MeSH
- buněčné linie MeSH
- glykosylace MeSH
- HeLa buňky MeSH
- HL-60 buňky MeSH
- Jurkat buňky MeSH
- lidé MeSH
- lipoylace MeSH
- membránové mikrodomény metabolismus MeSH
- molekulová hmotnost MeSH
- mutageneze cílená MeSH
- nádorové buněčné linie MeSH
- posttranslační úpravy proteinů MeSH
- protein - isoformy fyziologie genetika chemie MeSH
- receptory TNF genetika chemie metabolismus MeSH
- rekombinantní proteiny genetika chemie metabolismus MeSH
- sekvenční delece MeSH
- terciární struktura proteinů MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- práce podpořená grantem MeSH
TNF-related apoptosis-inducing ligand (TRAIL) is a proapoptotic cytokine implicated in cancer cell surveillance. A potential of TRAIL as a cancer-specific therapeutic agent has been proposed, either as a single agent or in combination with chemotherapy. Prolonged exposure of TRAIL-sensitive leukemia cell line, wild-type (WT) HL60 cells to recombinant soluble TRAIL or to cytostatic agents, cytarabine and idarubicin, resulted in the establishment of resistant subclones with distinct phenotypic features. The TRAIL resistant HL60 subclones were characterized by decreased expression of TRAIL and TNFalpha death receptors. These resistant subclones had impaired activation of caspases 8 and 10 in response to TRAIL and TNFalpha, decreased TRAIL-induced nuclear translocation of NFkappaB RelA/p65, and dysregulation of the expression of several apoptosis regulators. Among the TRAIL resistant HL60 subclones we identified two separate phenotypes that differed in the expression of CD14, osteoprotegerin, and several apoptosis regulators. Both these TRAIL resistant HL60 subclones were resistant to TNFalpha, suggesting disruption of the extrinsic apoptotic pathway, but not to cytostatic agents, cytarabine and idarubicin. The concurrently derived HL60 subclones were cytarabine and idarubicin-resistant but remained sensitive to TRAIL-induced apoptosis. We identified distinct pathways for the development of HL60 leukemia cell resistance to apoptosis induction. These findings are relevant for the design of more effective strategies for leukemia therapy.
- MeSH
- akutní promyelocytární leukemie metabolismus patologie MeSH
- apoptóza MeSH
- chemorezistence MeSH
- cytarabin farmakologie MeSH
- financování organizované MeSH
- HL-60 buňky MeSH
- idarubicin farmakologie MeSH
- kaspasy metabolismus účinky léků MeSH
- lidé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- protein TRAIL farmakologie MeSH
- protein-serin-threoninkinasy metabolismus účinky léků MeSH
- proteiny regulující apoptózu metabolismus účinky léků MeSH
- receptory TNF metabolismus účinky léků MeSH
- rekombinantní proteiny farmakologie MeSH
- TNF-alfa farmakologie MeSH
- TRAIL receptory metabolismus účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
