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Trends in Endocrinology and Metabolism:... Oct 20092-Methoxyestradiol (2-ME) is a biologically active metabolite of 17beta-estradiol that appears to inhibit key processes associated with cell replication in vitro. The... (Review)
Review
2-Methoxyestradiol (2-ME) is a biologically active metabolite of 17beta-estradiol that appears to inhibit key processes associated with cell replication in vitro. The molecule has been suggested to have potent growth-inhibitory effects on proliferating cells, including smooth muscle cells and endothelial cells, and may be antiangiogenic. Because of these potential roles for 2-ME, its lack of cytotoxicity and low estrogenic activity, we hypothesize that 2-ME could be a valuable therapeutic molecule for prevention and treatment of cardiovascular diseases. Whether 2-ME is as effective in vivo as it is in vitro at modulating vascular processes remains controversial. Here we discuss recent developments regarding mechanisms by which 2-ME might regulate vascular activity and angiogenesis and speculate on the therapeutic implications of these developments.
Topics: 2-Methoxyestradiol; Animals; Cardiovascular Diseases; Estradiol; Humans; Models, Biological; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Neovascularization, Pathologic; Tubulin Modulators
PubMed: 19734053
DOI: 10.1016/j.tem.2009.04.007 -
Angewandte Chemie (International Ed. in... Jun 2021Tubulin plays essential roles in vital cellular activities and is the target of a wide range of proteins and ligands. Here, using a combined computational and...
Tubulin plays essential roles in vital cellular activities and is the target of a wide range of proteins and ligands. Here, using a combined computational and crystallographic fragment screening approach, we addressed the question of how many binding sites exist in tubulin. We identified 27 distinct sites, of which 11 have not been described previously, and analyzed their relationship to known tubulin-protein and tubulin-ligand interactions. We further observed an intricate pocket communication network and identified 56 chemically diverse fragments that bound to 10 distinct tubulin sites. Our results offer a unique structural basis for the development of novel small molecules for use as tubulin modulators in basic research applications or as drugs. Furthermore, our method lays down a framework that may help to discover new pockets in other pharmaceutically important targets and characterize them in terms of chemical tractability and allosteric modulation.
Topics: Allosteric Regulation; Binding Sites; Crystallography, X-Ray; Ligands; Molecular Dynamics Simulation; Protein Binding; Tubulin; Tubulin Modulators
PubMed: 33951246
DOI: 10.1002/anie.202100273 -
Journal of the American College of... Nov 2013Colchicine, a natural and ancient drug still used today, is traditionally considered the staple therapy for gout and a second-line treatment for pericarditis, as well as... (Review)
Review
Colchicine, a natural and ancient drug still used today, is traditionally considered the staple therapy for gout and a second-line treatment for pericarditis, as well as a basic part of familial Mediterranean fever and Behcet's disease management. It is commonly classified as an anti-inflammatory agent, although its mechanism of action does not involve the arachidonic acid pathway affected by non-steroid anti-inflammatory drugs and glucocorticoids. Colchicine inhibits microtubule polymerization by binding to tubulin, thus affecting any process that requires cytoskeletal changes, including cell mitosis and neutrophil motility. Recent studies suggest that colchicine may prove to be useful in a much wider spectrum of cardiovascular diseases than previously suspected, rekindling the interest in this old drug. In this review we briefly present the biochemical characteristics, mechanism of action and side-effects of colchicine, as well as examine what is currently known about the promising role of colchicine in cardiovascular medicine beyond pericardial disease.
Topics: Angioplasty; Animals; Atrial Fibrillation; Colchicine; Coronary Artery Disease; Heart Diseases; Humans; Pericarditis; Tubulin Modulators
PubMed: 24036026
DOI: 10.1016/j.jacc.2013.08.726 -
Molecular Cancer Therapeutics Feb 2014Natural compounds that target microtubules and disrupt the normal function of the mitotic spindle have proven to be one of the best classes of cancer chemotherapeutic... (Review)
Review
Natural compounds that target microtubules and disrupt the normal function of the mitotic spindle have proven to be one of the best classes of cancer chemotherapeutic drugs available in clinics to date. There is increasing evidence showing that even minor alteration of microtubule dynamics can engage the spindle checkpoint, arresting cell-cycle progression at mitosis and subsequently leading to cell death. Our improved understanding of tumor biology and our continued appreciation for what the microtubule targeting agents (MTAs) can do have helped pave the way for a new era in the treatment of cancer. The effectiveness of these agents for cancer therapy has been impaired, however, by various side effects and drug resistance. Several new MTAs have shown potent activity against the proliferation of various cancer cells, including resistance to the existing MTAs. Sustained investigation of the mechanisms of action of MTAs, development and discovery of new drugs, and exploring new treatment strategies that reduce side effects and circumvent drug resistance could provide more effective therapeutic options for patients with cancer. This review focuses on the successful cancer chemotherapy from natural compounds in clinical settings and the challenges that may abort their usefulness.
Topics: Antineoplastic Agents; Biological Products; Cell Cycle Checkpoints; Humans; Microtubules; Models, Biological; Neoplasms; Treatment Outcome; Tubulin Modulators
PubMed: 24435445
DOI: 10.1158/1535-7163.MCT-13-0791 -
Clinics (Sao Paulo, Brazil) Dec 2018Cell cycle control genes are frequently mutated in cancer cells, which usually display higher rates of proliferation than normal cells. Dysregulated mitosis leads to... (Review)
Review
Cell cycle control genes are frequently mutated in cancer cells, which usually display higher rates of proliferation than normal cells. Dysregulated mitosis leads to genomic instability, which contributes to tumor progression and aggressiveness. Many drugs that disrupt mitosis have been studied because they induce cell cycle arrest and tumor cell death. These antitumor compounds are referred to as antimitotics. Vinca alkaloids and taxanes are natural products that target microtubules and inhibit mitosis, and their derivatives are among the most commonly used drugs in cancer therapy worldwide. However, severe adverse effects such as neuropathies are frequently observed during treatment with microtubule-targeting agents. Many efforts have been directed at developing improved antimitotics with increased specificity and decreased likelihood of inducing side effects. These new drugs generally target specific components of mitotic regulation that are mainly or exclusively expressed during cell division, such as kinases, motor proteins and multiprotein complexes. Such small molecules are now in preclinical studies and clinical trials, and many are products or derivatives from natural sources. In this review, we focused on the most promising targets for the development of antimitotics and discussed the advantages and disadvantages of these targets. We also highlighted the novel natural antimitotic agents under investigation by our research group, including combretastatins, withanolides and pterocarpans, which show the potential to circumvent the main issues in antimitotic therapy.
Topics: Antimitotic Agents; Antineoplastic Agents; Biological Products; Drug Development; Humans; Mitosis; Neoplasms
PubMed: 30540125
DOI: 10.6061/clinics/2018/e813s -
International Journal of Molecular... Sep 2022ATP-binding cassette subfamily G and tubulin pharmacological mechanisms decrease the effectiveness of anticancer drugs by modulating drug absorption and by creating... (Review)
Review
ATP-binding cassette subfamily G and tubulin pharmacological mechanisms decrease the effectiveness of anticancer drugs by modulating drug absorption and by creating tubulin assembly through polymerization. A series of natural and synthetic chalcones have been reported to have very good anticancer activity, with a half-maximal inhibitory concentration lower than 1 µM. By modulation, it is observed in case of the first mechanism that methoxy substituents on the aromatic cycle of acetophenone residue and substitution of phenyl nucleus by a heterocycle and by methoxy or hydroxyl groups have a positive impact. To inhibit tubulin, compounds bind to colchicine binding site. Presence of methoxy groups, amino groups or heterocyclic substituents increase activity.
Topics: Acetophenones; Adenosine Triphosphate; Antineoplastic Agents; Cell Proliferation; Chalcone; Chalcones; Colchicine; Molecular Structure; Structure-Activity Relationship; Tubulin; Tubulin Modulators
PubMed: 36232899
DOI: 10.3390/ijms231911595 -
Medicinal Research Reviews Jul 2019Microtubule (MT)-targeting agents are highly successful drugs as chemotherapeutic agents, and this is attributed to their ability to target MT dynamics and interfere... (Review)
Review
Microtubule (MT)-targeting agents are highly successful drugs as chemotherapeutic agents, and this is attributed to their ability to target MT dynamics and interfere with critical cellular functions, including, mitosis, cell signaling, intracellular trafficking, and angiogenesis. Because MT dynamics vary in the different stages of the cell cycle, these drugs tend to be the most effective against mitotic cells. While this class of drug has proven to be effective against many cancer types, significant hurdles still exist and include overcoming aspects such as dose limited toxicities and the development of resistance. Newer generations of developed drugs attack these problems and alternative approaches such as the development of dual tubulin and kinase inhibitors are being investigated. This approach offers the potential to show increased efficacy and lower toxicities. This review covers different categories of MT-targeting agents, recent advances in dual inhibitors, and current challenges for this drug target.
Topics: Antineoplastic Agents; Humans; Microtubules; Neoplasms; Tubulin Modulators
PubMed: 30746734
DOI: 10.1002/med.21568 -
Bioorganic & Medicinal Chemistry Sep 2014Microtubules (MTs), cytoskeletal elements found in all mammalian cells, play a significant role in cell structure and in cell division. They are especially critical in... (Review)
Review
Microtubules (MTs), cytoskeletal elements found in all mammalian cells, play a significant role in cell structure and in cell division. They are especially critical in the proper functioning of post-mitotic central nervous system neurons, where MTs serve as the structures on which key cellular constituents are trafficked in axonal projections. MTs are stabilized in axons by the MT-associated protein tau, and in several neurodegenerative diseases, including Alzheimer's disease, frontotemporal lobar degeneration, and Parkinson's disease, tau function appears to be compromised due to the protein dissociating from MTs and depositing into insoluble inclusions referred to as neurofibrillary tangles. This loss of tau function is believed to result in alterations of MT structure and function, resulting in aberrant axonal transport that likely contributes to the neurodegenerative process. There is also evidence of axonal transport deficiencies in other neurodegenerative diseases, including amyotrophic lateral sclerosis and Huntington's disease, which may result, at least in part, from MT alterations. Accordingly, a possible therapeutic strategy for such neurodegenerative conditions is to treat with MT-stabilizing agents, such as those that have been used in the treatment of cancer. Here, we review evidence of axonal transport and MT deficiencies in a number of neurodegenerative diseases, and summarize the various classes of known MT-stabilizing agents. Finally, we highlight the growing evidence that small molecule MT-stabilizing agents provide benefit in animal models of neurodegenerative disease and discuss the desired features of such molecules for the treatment of these central nervous system disorders.
Topics: Animals; Humans; Microtubules; Molecular Structure; Neurodegenerative Diseases; Structure-Activity Relationship; Tubulin Modulators
PubMed: 24433963
DOI: 10.1016/j.bmc.2013.12.046 -
Open Biology Nov 2017Paclitaxel is a successful anti-cancer drug that kills cancer cells in two-dimensional culture through perturbation of mitosis, but whether it causes tumour regression... (Review)
Review
Paclitaxel is a successful anti-cancer drug that kills cancer cells in two-dimensional culture through perturbation of mitosis, but whether it causes tumour regression by anti-mitotic actions is controversial. Drug candidates that specifically target mitosis, including inhibitors of kinesin-5, AurkA, AurkB and Plk1, disappointed in the clinic. Current explanations for this discrepancy include pharmacokinetic differences and hypothetical interphase actions of paclitaxel. Here, we discuss post-mitotic micronucleation as a special activity of taxanes that might explain their higher activity in solid tumours. We review data showing that cells which exit mitosis in paclitaxel are highly micronucleated and suffer post-mitotic DNA damage, and that these effects are much stronger for paclitaxel than kinesin-5 inhibitors. We propose that post-mitotic micronucleation promotes inflammatory signalling via cGAS-STING and other pathways. In tumours, this signalling may recruit cytotoxic leucocytes, damage blood vessels and prime T-cell responses, leading to whole-tumour regression. We discuss experiments that are needed to test the micronucleation hypothesis, and its implications for novel anti-mitotic targets and enhancement of taxane-based therapies.
Topics: Animals; Anti-Inflammatory Agents; Antimitotic Agents; Antineoplastic Agents; Humans; Micronuclei, Chromosome-Defective; Neoplasms; Paclitaxel
PubMed: 29142107
DOI: 10.1098/rsob.170182 -
Internal and Emergency Medicine Sep 2021The emerging role of colchicine in the treatment of cardiovascular diseases is a strong demand for a comprehensive understanding of its efficacy and safety. This... (Review)
Review
The emerging role of colchicine in the treatment of cardiovascular diseases is a strong demand for a comprehensive understanding of its efficacy and safety. This meta-analysis and systematic review aimed to study the efficacy in the reduction of adverse cardiovascular outcomes (CO), and the risk of colchicine-related adverse events (CRAEs). Fourteen thousand and nine eighty three patients from 22 randomized controlled trials (RCTs) were included, 9 in patients with coronary artery disease-CAD, 9 in patients with pericarditis, 4 in patients with atrial fibrillation-AF or heart failure. Colchicine was efficacious in the reduction of adverse CO across different settings: pericardial diseases (reduced risk of recurrent pericarditis, 17.6% vs. 35%, RR 0.50, 95% CI 0.41-0.61), CAD (reduced risk of cardiac death, myocardial infarction, stroke,coronary revascularization or hospitalization, 6.1% vs. 8.5%, RR 0.73, 95% CI 0.64-0.83), AF (reduced risk of arrhythmia recurrence, 14.2% vs. 22.7%, RR 0.62, 95% CI 0.44-0.88). Colchicine was associated with increased risk of gastrointestinal CRAEs (11.2% vs. 8.8%, RR 1.87, 95% CI 1.41-2.47) and drug discontinuation (5.4% vs. 3.7%, RR 1.58, 95% CI 1.25-1.99). In both cases, the risk was proportional to the daily dose or duration of treatment, possibly due to early drug discontinuation or tolerance. Other CRAEs (muscle-related, liver,hematologic,cutaneous, infections) were not increased by colchicine, as long as all-cause death (2.2% vs. 1.9%, RR 1.11, 95% CI 0.79-1.54) or non-cardiovascular death (1.5% vs. 1%, RR 1.43, 95% CI 0.93-2.19). Colchicine is efficacious and safe for the treatment of cardiovascular diseases. The risk of gastrointestinal CRAEs and drug discontinuation is not significant if colchicine is used at lower doses (0.5 mg daily) or for longer periods of time (> 6 months).
Topics: Aged; Cardiovascular Diseases; Colchicine; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Patient Safety; Risk Reduction Behavior; Treatment Outcome; Tubulin Modulators
PubMed: 33704674
DOI: 10.1007/s11739-021-02654-7