As the world population ages, there will be an increasing need for effective therapies for aging-associated neurodegenerative disorders, which remain untreatable. Dementia due to Alzheimer's disease (AD) is one of the leading neurological diseases in the aging population. Current therapeutic approaches to treat this disorder are solely symptomatic, making the need for new molecular entities acting on the causes of the disease extremely urgent. One of the potential solutions is to use compounds that are already in the market. The structures have known pharmacokinetics, pharmacodynamics, toxicity profiles, and patient data available in several countries. Several drugs have been used successfully to treat diseases different from their original purposes, such as autoimmunity and peripheral inflammation. Herein, we divulge the repurposing of drugs in the area of neurodegenerative diseases, focusing on the therapeutic potential of antineoplastics to treat dementia due to AD and dementia. We briefly touch upon the shared pathological mechanism between AD and cancer and drug repurposing strategies, with a focus on artificial intelligence. Next, we bring out the current status of research on the development of drugs, provide supporting evidence from retrospective, clinical, and preclinical studies on antineoplastic use, and bring in new areas, such as repurposing drugs for the prion-like spreading of pathologies in treating AD.

• MeSH
• Alzheimerova nemoc * farmakoterapie   MeSH
• antitumorózní látky * farmakologie   terapeutické užití   chemie   MeSH
• demence * farmakoterapie   MeSH
• lidé MeSH
• pozorovací studie jako téma MeSH
• přehodnocení terapeutických indikací léčivého přípravku * MeSH
• preklinické hodnocení léčiv MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

No effective therapeutics to treat neurodegenerative diseases exist, despite significant attempts to find drugs that can reduce or rescue the debilitating symptoms of tauopathies such as Alzheimer's disease, Parkinson's disease, frontotemporal dementia, amyotrophic lateral sclerosis, or Pick's disease. A number of in vitro and in vivo models exist for studying neurodegenerative diseases, including cell models employing induced-pluripotent stem cells, cerebral organoids, and animal models of disease. Recent research has focused on microtubulestabilizing agents, either natural products or synthetic compounds that can prevent the axonal destruction caused by tau protein pathologies. Although promising results have come from animal model studies using brainpenetrant natural product microtubule-stabilizing agents, such as paclitaxel analogs that can access the brain, epothilones B and D, and other synthetic compounds such as davunetide or the triazolopyrimidines, early clinical trials in humans have been disappointing. This review aims to summarize the research that has been carried out in this area and discuss the potential for the future development of an effective microtubule stabilizing drug to treat neurodegenerative disease.

• MeSH
• Alzheimerova nemoc * farmakoterapie   MeSH
• biologické přípravky * farmakologie   MeSH
• lidé MeSH
• mikrotubuly MeSH
• neurodegenerativní nemoci * farmakoterapie   MeSH
• proteiny tau MeSH
• tauopatie * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

HCT116 colorectal cancer cell sensitivity to peloruside A (PLA) in normoxia is not altered by hypoxia preconditioning of the cells. We examined whether the PLA effects were altered in hypoxia and whether the activity was dependent on p53. The cytotoxicity of PLA in wild-type HCT116 cells was largely unaffected by hypoxia; however, cells in which p53 was knocked out showed resistance. Knockout of the p21 gene had little effect on the activity of PLA in hypoxia. It was concluded that the response of cells to the microtubule-stabilizing agent PLA under hypoxic conditions is a p53-dependent process.

• MeSH
• bicyklické sloučeniny heterocyklické farmakologie   MeSH
• buněčná smrt účinky léků   MeSH
• HCT116 buňky MeSH
• hypoxie farmakoterapie   metabolismus   MeSH
• inhibitor p21 cyklin-dependentní kinasy metabolismus   MeSH
• kolorektální nádory farmakoterapie   metabolismus   MeSH
• laktony farmakologie   MeSH
• lidé MeSH
• mikrotubuly účinky léků   metabolismus   MeSH
• nádorové buněčné linie MeSH
• nádorový supresorový protein p53 metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem 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
• antitumorózní látky farmakologie   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
• vinkristin farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Microtubules, an important cytoskeletal protein involved in mitotic and non-mitotic functions of cells, are important targets in cancer therapy. Microtubule-stabilizing drugs like the taxanes are critical adjuvant and palliative first-line therapies for the treatment of early, advanced and metastatic solid tumors of different lineages. Their adverse on- and off-target effects and high susceptibility to multidrug resistance, however, are major challenges encountered in the clinic in the treatment of solid cancers. Although biochemical resistance to microtubule-stabilizing drugs has been well characterized, molecular mechanisms that contribute to clinical resistance to taxanes in solid tumors still remain poorly understood and uncontrolled. The heterogeneous tumor microenvironment leads to greater diversity of resistance mechanisms to taxanes. Tumor hypoxia, a prominent feature of solid tumors, results in a broad range of effects on a number of cellular pathways and is one of the major contributors to the development of resistance to not only microtubule-stabilizing drugs but also other anticancer drugs. In this review, we highlight the potential role of hypoxia in the development of resistance to taxanes through mechanisms that involve altering the cell cycle, changing the properties of microtubules, and inducing the overexpression of gene products that contribute to drug resistance. Hypoxia-induced challenges described in this review are not limited to microtubule-stabilizing drugs alone, but in many cases also impact on treatment with non-microtubule-targeting anticancer drugs.

• MeSH
• buněčný cyklus účinky léků   MeSH
• chemorezistence účinky léků   MeSH
• faktor 1 indukovatelný hypoxií - podjednotka alfa genetika   MeSH
• hypoxie buňky účinky léků   MeSH
• lidé MeSH
• mikrotubuly účinky léků   genetika   MeSH
• nádorové mikroprostředí MeSH
• nádory farmakoterapie   genetika   patologie   MeSH
• nežádoucí účinky léčiv MeSH
• taxoidy terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Polyglutamylation of tubulin and other non-tubulin substrates is a reversible posttranslational modification brought about by tubulin tyrosine-like ligases. Altered polyglutamylation is linked to tumorigenesis and resistance to chemotherapeutic drugs that target the microtubule, and therefore is a potential pharmacological target in cancer therapy. Despite the large amount of research focused on the development of anticancer agents, only a small number of well-characterized inhibitors of polyglutamylases have been identified, including the phosphinic acid-based inhibitors of Ttll7. In this minireview, we summarize the role of polyglutamylation in cancer, and draw attention to the largely unexplored area of polyglutamylase inhibition in the treatment of cancer.

• MeSH
• antitumorózní látky farmakologie   MeSH
• chemorezistence * MeSH
• karcinogeneze * MeSH
• lidé MeSH
• mikrotubuly účinky léků   enzymologie   MeSH
• nádory farmakoterapie   enzymologie   patologie   MeSH
• peptidsynthasy genetika   metabolismus   MeSH
• posttranslační úpravy proteinů MeSH
• signální transdukce MeSH
• tubulin metabolismus   MeSH
• tyrosin metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

An important aspect of synaptic plasticity in the brain is axonal transport of essential components such as mitochondria from the soma to the synapse. For uninterrupted transport of cellular cargo down the axon, functional microtubules are required. Altered microtubule dynamics induced by changes in expression of microtubule-associated tau protein affects normal microtubule function and interferes with axonal transport. Here we investigate the effects of the nontaxoid-binding-site microtubule-stabilizing agents peloruside A (PelA) and laulimalide, compared with the taxoid-site-binding agents paclitaxel (Ptx) and ixabepilone, on axonal transport of mitochondria in 1-day-old rat pup cerebral cortical neuron cultures. The differences in effects of these two types of compound on mitochondrial trafficking were specifically compared under conditions of excess tau expression. PelA and laulimalide had no adverse effects on their own on mitochondrial transport compared with Ptx and ixabepilone, which inhibited mitochondrial run length at higher concentrations. PelA, like Ptx, was able to partially reverse the blocked mitochondrial transport seen in ECFP-htau40-overexpressing neurons, although at higher concentrations of microtubule-stabilizing agent, the PelA response was improved over the Ptx response. These results support a neuroprotective effect of microtubule stabilization in maintaining axonal transport in neurons overexpressing tau protein and may be beneficial in reducing the severity of neurodegenerative diseases such as Alzheimer's disease.

• MeSH
• axonální transport účinky léků   MeSH
• bicyklické sloučeniny heterocyklické farmakologie   MeSH
• epothilony farmakologie   MeSH
• krysa rodu rattus MeSH
• kultivované buňky MeSH
• laktony farmakologie   MeSH
• lidé MeSH
• makrolidy farmakologie   MeSH
• membránové proteiny genetika   metabolismus   MeSH
• mikrotubuly účinky léků   MeSH
• mitochondrie fyziologie   MeSH
• modulátory tubulinu farmakologie   MeSH
• mozková kůra cytologie   MeSH
• neurony účinky léků   ultrastruktura   MeSH
• novorozená zvířata MeSH
• paclitaxel farmakologie   MeSH
• potkani Sprague-Dawley MeSH
• transfekce MeSH
• zelené fluorescenční proteiny genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• diagnostické techniky radioisotopové * MeSH
• dítě MeSH
• kojenec MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• Publikační typ
• monografie MeSH

• Konspekt
• Pediatrie
• NLK Obory
• pediatrie
• radiologie, nukleární medicína a zobrazovací metody