DNA methylation plays a pivotal role in the etiology of cancer by mediating epigenetic silencing of cancer-related genes. Since the relationship between aberrant DNA methylation and cancer has been understood, there has been an explosion of research at developing anti-cancer therapies that work by inhibiting DNA methylation. From the discovery of first DNA hypomethylating drugs in the 1980s to recently discovered second generation pro-drugs, exceedingly large number of studies have been published that describe the DNA hypomethylation-based anti-neoplastic action of these drugs in various stages of the pre-clinical investigation and advanced stages of clinical development. This review is a comprehensive report of the literature published in past 40 years, on so far discovered nucleosidic DNA methylation inhibitors in chronological order. The review will provide a complete insight to the readers about the mechanisms of action, efficacy to demethylate and re-express various cancer-related genes, anti-tumor activity, cytotoxicity profile, stability, and bioavailability of these drugs. The review further presents the far known mechanisms of primary and secondary resistance to azanucleoside drugs. Finally, the review highlights the ubiquitous role of DNA hypomethylating epi-drugs as chemosensitizers and/or priming agents, and recapitulate the combinatorial cancer preventive effects of these drugs with other epigenetic agents, conventional chemo-drugs, or immunotherapies. This comprehensive review analyzes the beneficial characteristics and drawbacks of nucleosidic DNA methylation inhibitors, which will assist the pre-clinical and clinical researchers in the design of future experiments to improve the therapeutic efficacy of these drugs and circumvent the challenges in the path of successful epigenetic therapy.

• MeSH
• azacytidin analogy a deriváty   farmakologie   MeSH
• chemorezistence MeSH
• DNA-(cytosin-5)-methyltransferasa 1 antagonisté a inhibitory   MeSH
• lidé MeSH
• metylace DNA účinky léků   MeSH
• nukleosidy farmakologie   MeSH
• objevování léků * MeSH
• protinádorové látky farmakologie   terapeutické užití   MeSH
• thioguanin farmakologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

BACKGROUND: Hypoxia is a prominent feature of solid tumors, dramatically remodeling microtubule structures and cellular pathways and contributing to paclitaxel resistance. Peloruside A (PLA), a microtubule-targeting agent, has shown promising anti-tumor effects in preclinical studies. Although it has a similar mode of action to paclitaxel, it binds to a distinct site on β-tubulin that differs from the classical taxane site. In this study, we examined the unexplored effects of PLA in hypoxia-conditioned colorectal HCT116 cancer cells. METHODS: Cytotoxicity of PLA was determined by cell proliferation assay. The effects of a pre-exposure to hypoxia on PLA-induced cell cycle alterations and apoptosis were examined by flow cytometry, time-lapse imaging, and western blot analysis of selected markers. The hypoxia effect on stabilization of microtubules by PLA was monitored by an intracellular tubulin polymerization assay. RESULTS: Our findings show that the cytotoxicity of PLA is not altered in hypoxia-conditioned cells compared to paclitaxel and vincristine. Furthermore, hypoxia does not alter PLA-induced microtubule stabilization nor the multinucleation of cells. PLA causes cyclin B1 and G2/M accumulation followed by apoptosis. CONCLUSIONS: The cellular and molecular effects of PLA have been determined in normoxic conditions, but there are no reports of PLA effects in hypoxic cells. Our findings reveal that hypoxia preconditioning does not alter the sensitivity of HCT116 to PLA. GENERAL SIGNIFICANCE: These data report on the cellular and molecular effects of PLA in hypoxia-conditioned cells for the first time, and will encourage further exploration of PLA as a promising anti-tumor agent.

• MeSH
• apoptóza účinky léků   MeSH
• bicyklické sloučeniny heterocyklické farmakologie   MeSH
• buňky HT-29 MeSH
• cyklin B1 metabolismus   MeSH
• HCT116 buňky MeSH
• hypoxie buňky * MeSH
• kontrolní body buněčného cyklu účinky léků   MeSH
• laktony farmakologie   MeSH
• lidé MeSH
• mikrotubuly účinky léků   MeSH
• paclitaxel farmakologie   MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky farmakologie   MeSH
• vinkristin farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: Various cerebrospinal fluid (CSF) biomarkers are being studied to improve the sensitivity and specificity of the diagnostic methods for amyotrophic lateral sclerosis (ALS). AIMS OF THE STUDY: The aim of our study was to establish the CSF levels of chromogranin A (CgA) and phosphorylated neurofilament heavy chain (pNF-H) in patients with ALS in order to assess these proteins as possible biomarkers of ALS. METHODS: Cerebrospinal fluid levels of CgA and pNF-H were examined and mutually compared in 15 patients with sporadic ALS and 16 gender- and age-matched controls. RESULTS: Lumbar CSF CgA levels were increased in the patients with ALS compared to the controls (median 235 vs 138, P=.031). Lumbar CSF pNF-H levels were significantly increased in the patients with ALS compared to the control group (median 3091 vs 213, P<.0001). CONCLUSIONS: Identifying CSF biomarkers in ALS is important in order to establish the diagnosis in the early stages of the disease. pNF-H seems to be a good biomarker for the diagnosis of ALS. If confirmed on a larger group of patients, CgA may also become useful in the diagnosis of sporadic ALS.

• MeSH
• amyotrofická laterální skleróza diagnóza   MeSH
• biologické markery MeSH
• chromogranin A MeSH
• fosforylace MeSH
• lidé středního věku MeSH
• lidé MeSH
• neurofilamentové proteiny MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• senzitivita a specificita MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Combretastatin A-4 (CA-4) is a highly cytotoxic natural product and several derivatives have been prepared which underwent clinical trial. These investigations revealed that the cis-stilbene moiety of the natural product is prone to undergo cis/trans isomerization under physiological conditions, reducing the overall activity of the drug candidates. Herein, we report the preparation of cis-restrained carbocyclic analogs of CA-4. The compounds, which differ by the size and hybridization of the carbocyclic ring have been evaluated for their cytotoxic properties and their ability to inhibit tubulin polymerization. Biological data, supported by molecular docking studies, identified cyclobutenyl and cyclobutyl derivatives of the natural product as highly promising drug candidates.

• MeSH
• kontrolní body fáze G2 buněčného cyklu účinky léků   MeSH
• lidé MeSH
• modulátory tubulinu chemická syntéza   metabolismus   farmakologie   MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• protinádorové látky chemická syntéza   metabolismus   farmakologie   MeSH
• screeningové testy protinádorových léčiv MeSH
• simulace molekulového dockingu MeSH
• stilbeny chemická syntéza   metabolismus   farmakologie   MeSH
• tubulin metabolismus   MeSH
• vazba proteinů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects normal functions of the brain. Currently, AD is one of the leading causes of death in developed countries and the only one of the top ten diseases without a means to prevent, cure, or significantly slow down its progression. Therefore, newer therapeutic concepts are urgently needed to improve survival and the quality of life of AD patients. Microtubule affinity-regulating kinases (MARKs) regulate tau-microtubule binding and play a crucial role in neurons. However, their role in hyperphosphorylation of tau makes them potential druggable target for AD therapy. Despite the relevance of MARKs in AD pathogenesis, only a few small molecules are known to have anti-MARK activity and not much has been done to progress these compounds into therapeutic candidates. But given the diverse role of MARKs, the specificity of novel inhibitors is imperative for their successful translation from bench to bedside. In this regard, a recent co-crystal structure of MARK4 in association with a pyrazolopyrimidine-based inhibitor offers a potential scaffold for the development of more specific MARK inhibitors. In this manuscript, we review the biological role of MARKs in health and disease, and draw attention to the largely unexplored area of MARK inhibitors for AD.

• MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   patologie   MeSH
• antigeny bakteriální terapeutické užití   MeSH
• azepiny chemie   terapeutické užití   MeSH
• bakteriální proteiny terapeutické užití   MeSH
• inhibitory proteinkinas chemie   terapeutické užití   MeSH
• lidé MeSH
• methylenová modř chemie   terapeutické užití   MeSH
• neurony metabolismus   MeSH
• protein-serin-threoninkinasy antagonisté a inhibitory   metabolismus   MeSH
• proteiny tau antagonisté a inhibitory   metabolismus   MeSH
• pyrazoly chemie   terapeutické užití   MeSH
• pyridiny chemie   terapeutické užití   MeSH
• pyrroly chemie   terapeutické užití   MeSH
• staurosporin chemie   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Alzheimerova choroba (AD) je progresivní mozkové onemocnění, které poškozuje a nakonec ničí mozkové buňky, což vede ke ztrátě paměti, myšlení a poškození dalších mozkových funkcí. V současné době je AD jednou z hlavních příčin úmrtí ve vyspělých zemích a jediná z první desítky nemocí, u které nemáme k dispozici prostředky na léčbu, prevenci nebo alespoň k významnému zpomalení progrese. Z těchto důvodů se intenzivně hledají nové terapeutické postupy pro zlepšení přežití a kvality života pacientů s AD a jejich rodin. Náš předchozí výzkum vedl k identifikaci nových selektivních nukleosidových inhibitorů MARK4 kinázy, která je zapojená v rozvoji patologie u AD. V předkládaném projektu navrhujeme komplexní translační výzkum vedoucí k syntéze a ověřování biologické aktivity syntetických inhibitorů MARK4 kinázy v in vitro anebo in vivo podmínkách s využitím zvířecích i lidských modelů AD a identifikaci preklinických kandidátů léčiv proti Alzheimerově chorobě.; Alzheimer disease (AD) is a progressive brain disorder that damages and eventually destroys brain cells, leading to a loss of memory, thinking and other brain functions. Currently, AD is one of the major cause of death in developed countries and the only one of the top ten without a means to prevent, cure or significantly slow its progression. Therefore, the new therapeutic concepts are urgently needed to improve survival and quality of life for AD patients and families. Our previous work resulted in identification of novel selective nucleoside based inhibitors of MARK4 kinase, which has been implicated in development of AD pathology. Here we propose complex translational research leading to synthesis and validation of biological activities of MARK4 inhibitors under both in vitro and in vivo conditions using animal and human models of AD and identification of preclinical candidates for anti-Alzheimer drugs.

• MeSH
• Alzheimerova nemoc farmakoterapie   MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• nukleosidy terapeutické užití   MeSH
• nukleotidy terapeutické užití   MeSH
• translační biomedicínský výzkum MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• neurologie
• farmacie a farmakologie
• NLK Publikační typ
• závěrečné zprávy o řešení grantu AZV MZ ČR