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International Journal of Molecular... Aug 2017Taxol, an antitumor drug with significant activity, is the first microtubule stabilizing agent described in the literature. This short review of the mechanism of action... (Review)
Review
Taxol, an antitumor drug with significant activity, is the first microtubule stabilizing agent described in the literature. This short review of the mechanism of action of Taxol emphasizes the research done in the Horwitz' laboratory. It discusses the contribution of photoaffinity labeled analogues of Taxol toward our understanding of the binding site of the drug on the microtubule. The importance of hydrogen/deuterium exchange experiments to further our insights into the stabilization of microtubules by Taxol is addressed. The development of drug resistance, a major problem that arises in the clinic, is discussed. Studies describing differential drug binding to distinct β-tubulin isotypes are presented. Looking forward, it is suggested that the β-tubulin isotype content of a tumor may influence its responses to Taxol.
Topics: Animals; Antineoplastic Agents, Phytogenic; Binding Sites; Cell Survival; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Humans; Microtubules; Paclitaxel; Protein Binding; Protein Isoforms; Protein Subunits; Structure-Activity Relationship; Tubulin Modulators
PubMed: 28792473
DOI: 10.3390/ijms18081733 -
Cancer Research Oct 2022Tumor treating fields (TTFields), a new modality of cancer treatment, are electric fields transmitted transdermally to tumors. The FDA has approved TTFields for the... (Review)
Review
Tumor treating fields (TTFields), a new modality of cancer treatment, are electric fields transmitted transdermally to tumors. The FDA has approved TTFields for the treatment of glioblastoma multiforme and mesothelioma, and they are currently under study in many other cancer types. While antimitotic effects were the first recognized biological anticancer activity of TTFields, data have shown that tumor treating fields achieve their anticancer effects through multiple mechanisms of action. TTFields therefore have the ability to be useful for many cancer types in combination with many different treatment modalities. Here, we review the current understanding of TTFields and their mechanisms of action.
Topics: Antimitotic Agents; Brain Neoplasms; Electric Stimulation Therapy; Glioblastoma; Humans
PubMed: 35839284
DOI: 10.1158/0008-5472.CAN-22-0887 -
Pediatric Rheumatology Online Journal Jun 2016The syndrome of periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA syndrome) is the most common cause of periodic fever in childhood. The... (Review)
Review
The syndrome of periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA syndrome) is the most common cause of periodic fever in childhood. The current pharmacological treatment includes corticosteroids, which usually are efficacious in the management of fever episodes, colchicine, for the prophylaxis of febrile episodes, and other medication for which efficacy has not been proven so far. Tonsillectomy is an option for selected patients. Usually PFAPA syndrome resolves during adolescence, but there is increasing evidence that this condition may persist into adulthood.
Topics: Adolescent; Child; Colchicine; Disease Management; Fever; Glucocorticoids; Humans; Lymphadenitis; Neck; Periodicity; Pharyngitis; Stomatitis, Aphthous; Syndrome; Tonsillectomy; Tubulin Modulators
PubMed: 27349388
DOI: 10.1186/s12969-016-0101-9 -
International Journal of Molecular... Apr 2021Vincristine-induced peripheral neurotoxicity (VIPN) is a very common side effect of vincristine chemotherapy among pediatric patients with cancer. Neuropathy may be... (Review)
Review
Vincristine-induced peripheral neurotoxicity (VIPN) is a very common side effect of vincristine chemotherapy among pediatric patients with cancer. Neuropathy may be sensory, motor and/or autonomic, with consequent reduction, delay or discontinuation of vincristine-chemotherapy, but also pain, disability, reduced quality of life of patients and an increase in medical costs. Vincristine acts out its antineoplastic function by altering the normal assembly and disassembly of microtubules, with their consequent mitosis block and death. Vincristine leads to VIPN through a complex mechanism of damage, which occurs not only on the microtubules, but also on the endothelium and the mitochondria of nerve cells. Furthermore, both patient-related risk factors (age, race, ethnicity and genetic polymorphisms) and treatment-related risk factors (dose, time of infusion and drug-drug interactions) are involved in the pathogenesis of VIPN. There is a lack of consensus about the prophylaxis and treatment of VIPN among pediatric oncologic patients, despite several molecules (such as gabapentin, pyridoxine and pyridostigmine, glutamic acid and glutamine) having been already investigated in clinical trials. This review describes the molecular mechanisms of VIPN and analyzes the risk factors and the principal drugs adopted for the prophylaxis and treatment of VIPN in pediatric patients with cancer.
Topics: Animals; Antineoplastic Agents; Child; Humans; Neurotoxicity Syndromes; Peripheral Nervous System Diseases; Tubulin Modulators; Vincristine
PubMed: 33923421
DOI: 10.3390/ijms22084112 -
International Journal of Molecular... May 2022Antimitotic agents such as the clinically approved vinca alkaloids, taxanes and epothilone can arrest cell growth during interphase and are therefore among the most... (Review)
Review
Antimitotic agents such as the clinically approved vinca alkaloids, taxanes and epothilone can arrest cell growth during interphase and are therefore among the most important drugs available for treating cancer. These agents suppress microtubule dynamics and thus interfere with intracellular transport, inhibit cell proliferation and promote cell death. Because these drugs target biological processes that are essential to all cells, they face an additional challenge when compared to most other drug classes. General toxicity can limit the applicable dose and therefore reduce therapeutic benefits. Photopharmacology aims to avoid these side-effects by introducing compounds that can be applied globally to cells in their inactive form, then be selectively induced to bioactivity in targeted cells or tissue during a defined time window. This review discusses photoswitchable analogues of antimitotic agents that have been developed by combining different photoswitchable motifs with microtubule-stabilizing or microtubule-destabilizing agents.
Topics: Antimitotic Agents; Antineoplastic Agents; Humans; Microtubules; Neoplasms; Vinca Alkaloids
PubMed: 35628467
DOI: 10.3390/ijms23105657 -
Current Oncology Reports Feb 2021Cancer and heart disease are the leading causes of mortality in the USA. Advances in cancer therapies, namely, the development and use of chemotherapeutic agents alone... (Review)
Review
PURPOSE OF REVIEW
Cancer and heart disease are the leading causes of mortality in the USA. Advances in cancer therapies, namely, the development and use of chemotherapeutic agents alone or in combination, are becoming increasingly prevalent.
RECENT FINDINGS
Many chemotherapeutic agents have been associated with adverse cardiovascular manifestations. The mechanisms of these sequelae remain incompletely understood. In particular, microtubule inhibitor (MTI) agents have been related to the development of heart failure, myocardial ischemia, and conduction abnormalities. At present, there are no guidelines for patients undergoing MTI therapy as it pertains to both preventative and mitigatory strategies for cardiovascular complications. We conducted a literature review focusing on content related to the use of MTIs and their effect on the cardiovascular system. MTIs have been associated with various forms of cardiotoxicity, and fatal cardiotoxicities are rare. The most well-described cardiotoxicities are brady- and tachyarrhythmias. The co-administration of anthracycline-based agents with MTIs can increase the risk of cardiotoxicity.
Topics: Cardiotoxicity; Heart Diseases; Humans; Neoplasms; Tubulin Modulators
PubMed: 33582937
DOI: 10.1007/s11912-021-01014-0 -
Journal of Cell Science Feb 2022PCTAIRE1 (also known as CDK16) is a serine-threonine kinase implicated in physiological processes like neuronal development, vesicle trafficking, spermatogenesis and...
PCTAIRE1 (also known as CDK16) is a serine-threonine kinase implicated in physiological processes like neuronal development, vesicle trafficking, spermatogenesis and cell proliferation. However, its exact role in cell division remains unclear. In this study, using a library screening approach, we identified PCTAIRE1 among several candidates that resisted mitotic arrest and mitotic cell death induced by polyomavirus small T (PolST) expression in mammalian cells. Our study showed that PCTAIRE1 is a mitotic kinase that localizes at centrosomes during G2 and at spindle poles as the cells enter mitosis, and then at the midbody during cytokinesis. We also report that PCTAIRE1 protein levels fluctuate through the cell cycle and reach their peak at mitosis, during which there is an increase in PCTAIRE1 phosphorylation as well. Interestingly, knockdown of PCTAIRE1 resulted in aberrant mitosis by interfering with spindle assembly and chromosome segregation. Further, we found that PCTAIRE1 promotes resistance of cancer cells to antimitotic drugs, and this underscores the significance of PCTAIRE1 as a potential drug target for overcoming chemotherapeutic resistance. Taken together, these studies establish PCTAIRE1 as a critical mediator of mitotic progression and highlight its role in chemotherapeutic resistance. This article has an associated First Person interview with the first author of the paper.
Topics: Animals; Antimitotic Agents; Cell Cycle Proteins; Centrosome; Chromosome Segregation; HeLa Cells; Humans; Male; Mitosis; Phosphorylation; Protein Serine-Threonine Kinases; Spindle Apparatus
PubMed: 35044463
DOI: 10.1242/jcs.258831 -
Cancer Chemotherapy and Pharmacology Dec 2015Cancer is a complex disease since it is adaptive in such a way that it can promote proliferation and invasion by means of an overactive cell cycle and in turn cellular... (Review)
Review
Cancer is a complex disease since it is adaptive in such a way that it can promote proliferation and invasion by means of an overactive cell cycle and in turn cellular division which is targeted by antimitotic drugs that are highly validated chemotherapy agents. However, antimitotic drug cytotoxicity to non-tumorigenic cells and multiple cancer resistance developed in response to drugs such as taxanes and vinca alkaloids are obstacles faced in both the clinical and basic research field to date. In this review, the classes of antimitotic compounds, their mechanisms of action and cancer cell resistance to chemotherapy and other limitations of current antimitotic compounds are highlighted, as well as the potential of novel 17-β estradiol analogs as cancer treatment.
Topics: Antimitotic Agents; Apoptosis; Biomarkers, Tumor; Cell Cycle; Cell Proliferation; Drug Resistance, Neoplasm; Humans; Neoplasms; Taxoids; Vinca Alkaloids
PubMed: 26563258
DOI: 10.1007/s00280-015-2903-8 -
Bioorganic & Medicinal Chemistry Sep 2014This review focuses on a relatively new class of microtubule stabilizers, the taccalonolides. The taccalonolides are highly oxygenated pentacyclic steroids isolated from... (Review)
Review
This review focuses on a relatively new class of microtubule stabilizers, the taccalonolides. The taccalonolides are highly oxygenated pentacyclic steroids isolated from plants of the genus Tacca. Originally identified in a cell-based phenotypic screen, the taccalonolides have many properties similar to other microtubule stabilizers. They increase the density of interphase microtubules, causing microtubule bundling, and form abnormal multi-polar mitotic spindles leading to mitotic arrest and, ultimately, apoptosis. However, the taccalonolides differ from other microtubule stabilizers in that they retain efficacy in taxane resistant cell lines and in vivo models. Binding studies with the newly identified, potent taccalonolide AJ demonstrated covalent binding to β-tubulin at or near the luminal and/or pore taxane binding site(s) which stabilizes microtubule protofilaments in a unique manner as compared to other microtubule stabilizers. The isolation and semi-synthesis of 21 taccalonolides helped to identify key structure activity relationships and the importance of multiple regions across the taccalonolide skeleton for optimal biological potency.
Topics: Antineoplastic Agents, Phytogenic; Humans; Microtubules; Models, Molecular; Molecular Conformation; Steroids; Structure-Activity Relationship; Tubulin Modulators
PubMed: 24491636
DOI: 10.1016/j.bmc.2014.01.012 -
BioMed Research International 2022L. var. argentea Andre is a plant widely spread in the region of Taza (North-East of Morocco); it is used in traditional phytotherapy against cancer, diabetes,...
L. var. argentea Andre is a plant widely spread in the region of Taza (North-East of Morocco); it is used in traditional phytotherapy against cancer, diabetes, inflammations, cardiovascular and respiratory diseases, and for the treatment of digestive disorders. The objective of our work is to contribute firstly, to the study of the antimitotic potential by the phytotest of and the evaluation of the antidiabetic activity of three enzymes (-amylase, -glucosidase, and -galactosidase) on nine aqueous and organic extracts prepared from the leaves of . In addition, a correlation study was carried out on the chemical composition and the antimitotic and antidiabetic activities of leaves. Then, we tested the acute toxicity of the decocted extract and the ethanolic extract. The results of the antimitotic activity showed that the decocted extract showed a higher inhibitory activity than the other aqueous extracts (IC = 9.624 × 10 ± 95.97 g/mL); for the organic extracts, the ethanolic extract and ethanolic macerated expressed the highest values for the cell growth inhibition test with an IC of 5.638 × 10 ± 22.61 and 5.599 × 10 ± 45.51 g/mL with statistically nonsignificant difference. Regarding the antidiabetic activity, the decocted showed a higher inhibitory activity than the other aqueous extracts for -amylase (IC = 1.781 · 10 ± 358.30 g/mL), -glucosidase (2.540 × 10 ± 3.14 g/mL), and -galactosidase (7.118 × 10 ± 16.13 g/mL); the ethanolic extract also revealed the highest inhibitory activity for -amylase (IC = 8.902 × 10 ± 57.81 g/mL), -glucosidase (2.216 × 10 ± 1.39 g/mL), and -galactosidase (2.003 × 10 ± 7.41 g/mL). A strong correlation was recorded between the antimitic activity and the inhibitory capacity of -galactosidase and between these two activities and the chemical composition of leaves. The acute toxicity study showed that the decocted and the ethanolic extract are weakly toxic with an LD greater than or equal to 5000 mg/kg. . could become a good source in traditional herbal medicine.
Topics: Hypoglycemic Agents; alpha-Glucosidases; Antimitotic Agents; Plant Extracts; alpha-Amylases; Arecaceae; beta-Galactosidase; Glycoside Hydrolase Inhibitors
PubMed: 36277886
DOI: 10.1155/2022/4303506