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European Journal of Medicinal Chemistry Jan 2018Antimitotic colchicine possesses low therapeutic index due to high toxicity effects in non-target cell. However, diverse colchicine analogs have been derivatized as... (Review)
Review
Antimitotic colchicine possesses low therapeutic index due to high toxicity effects in non-target cell. However, diverse colchicine analogs have been derivatized as intentions for toxicity reduction and structure-activity relationship (SAR) studying. Hybrid system of colchicine structure with nontoxic biofunctional compounds modified further affords a new entity in chemical structure with enhanced activity and selectivity. Moreover, nanocarrier formulation strategies have been used for colchicine delivery. This review paper focuses on colchicine nanoformulation, chemical synthesis of colchicine prodrugs and codrugs with different linkers, highlights linker chemical nature and biological activity of synthesized compounds. Additionally, classification of colchicine prodrugs based on type of conjugates is discussed, as biopolymers prodrugs, fluorescent prodrug, metal complexes prodrug, metal-labile prodrug and bioconjugate prodrug. Finally, we briefly summarized the biological importance of colchicine nanoformulation, colchicine prodrugs and codrugs.
Topics: Animals; Colchicine; Drug Design; Humans; Mitosis; Prodrugs; Structure-Activity Relationship; Tubulin Modulators
PubMed: 29274490
DOI: 10.1016/j.ejmech.2017.12.029 -
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 -
Italian Journal of Pediatrics Jan 2020Familial Mediterranean Fever, a monogenic autoinflammatory disease secondary to MEFV gene mutations in the chromosome 16p13, is characterized by recurrent self-limiting... (Review)
Review
Familial Mediterranean Fever, a monogenic autoinflammatory disease secondary to MEFV gene mutations in the chromosome 16p13, is characterized by recurrent self-limiting attacks of fever, arthritis, aphthous changes in lips and/or oral mucosa, erythema, serositis. It is caused by dysregulation of the inflammasome, a complex intracellular multiprotein structure, commanding the overproduction of interleukin 1. Familial Mediterranean Fever can be associated with other multifactorial autoinflammatory diseases, as vasculitis and Behçet disease.Symptoms frequently start before 20 years of age and are characterized by a more severe phenotype in patients who begin earlier.Attacks consist of fever, serositis, arthritis and high levels of inflammatory reactants: C-reactive protein, erythrocyte sedimentation rate, serum amyloid A associated with leucocytosis and neutrophilia. The symptom-free intervals are of different length.The attacks of Familial Mediterranean Fever can have a trigger, as infections, stress, menses, exposure to cold, fat-rich food, drugs.The diagnosis needs a clinical definition of the disease and a genetic confirmation. An accurate differential diagnosis is mandatory to exclude infective agents, autoimmune diseases, etc.In many patients there is no genetic confirmation of the disease; furthermore, some subjects with the relieve of MEFV mutations, show a phenotype not in line with the diagnosis of Familial Mediterranean Fever. For these reasons, diagnostic criteria were developed, as Tel Hashomer Hospital criteria, the "Turkish FMF Paediatric criteria", the "clinical classification criteria for autoinflammatory periodic fevers" formulated by PRINTO.The goals of the treatment are: prevention of attacks recurrence, normalization of inflammatory markers, control of subclinical inflammation in attacks-free intervals and prevention of medium and long-term complications, as amyloidosis. Colchicine is the first step in the treatment; biological drugs are effective in non-responder patients.The goal of this paper is to give a wide and broad review to general paediatricians on Familial Mediterranean Fever, with the relative diagnostic, clinical and therapeutic aspects.
Topics: Biomarkers; Child; Colchicine; Diagnosis, Differential; Familial Mediterranean Fever; Humans; Phenotype; Tubulin Modulators
PubMed: 31941537
DOI: 10.1186/s13052-019-0766-z -
The British Journal of Dermatology Feb 2018Colchicine is a treatment for gout that has been used for more than a millennium. It is the treatment of choice for familial Mediterranean fever and its associated... (Review)
Review
Colchicine is a treatment for gout that has been used for more than a millennium. It is the treatment of choice for familial Mediterranean fever and its associated complication, amyloidosis. The 2009 U.S. Food and Drug Administration approval of colchicine as a new drug had research consequences. Recent investigations with large cohorts of patients with gout who have been taking colchicine for years have demonstrated novel applications within oncology, immunology, cardiology and dermatology. Some emerging dermatological uses include the treatment of epidermolysis bullosa acquisita, leucocytoclastic vasculitis, aphthous stomatitis and others. In this work we relate the history and the new horizon of this ancient medicine.
Topics: Colchicine; Dermatologic Agents; Familial Mediterranean Fever; Gout; Gout Suppressants; History, 19th Century; History, 21st Century; History, Ancient; Humans; Rheumatic Diseases; Skin Diseases; Stomatitis, Aphthous; Tubulin Modulators
PubMed: 28832953
DOI: 10.1111/bjd.15896 -
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 -
Endocrine-related Cancer Sep 2017A colossal amount of basic research over the past few decades has provided unprecedented insights into the highly complex process of cell division. There is an... (Review)
Review
A colossal amount of basic research over the past few decades has provided unprecedented insights into the highly complex process of cell division. There is an ever-expanding catalog of proteins that orchestrate, participate and coordinate in the exquisite processes of spindle formation, chromosome dynamics and the formation and regulation of kinetochore microtubule attachments. Use of classical microtubule poisons has still been widely and often successfully used to combat a variety of cancers, but their non-selective interference in other crucial physiologic processes necessitate the identification of novel druggable components specific to the cell cycle/division pathway. Considering cell cycle deregulation, unscheduled proliferation, genomic instability and chromosomal instability as a hallmark of tumor cells, there lies an enormous untapped terrain that needs to be unearthed before a drug can pave its way from bench to bedside. This review attempts to systematically summarize the advances made in this context so far with an emphasis on endocrine-related cancers and the avenues for future progress to target mitotic mechanisms in an effort to combat these dreadful cancers.
Topics: Animals; Antimitotic Agents; Endocrine Gland Neoplasms; Humans; Microtubules; Mitosis; Tubulin
PubMed: 28615236
DOI: 10.1530/ERC-17-0080 -
Current Topics in Medicinal Chemistry 2014Epothilones are natural compounds isolated from a myxobacterium at the beginning of the 1990s, and showed a remarkable anti-neoplastic activity. They act through the... (Review)
Review
Epothilones are natural compounds isolated from a myxobacterium at the beginning of the 1990s, and showed a remarkable anti-neoplastic activity. They act through the same mechanism of action of paclitaxel, by stabilizing microtubules and inducing apoptosis. Although, their chemical structure, simpler than taxanes, makes them more suitable for derivatization. Their interesting pharmacokinetic and bioavailabilty profiles, and the activity against paclitaxel-resistant cell lines make them interesting therapeutic agents. Here a brief historical perspective of epothilones is presented, since their isolation, the identification of their mechanism of action and activity, to the recent clinical trials.
Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Clinical Trials as Topic; Drug Design; Epothilones; Humans; Microtubules; Mitosis; Molecular Docking Simulation; Neoplasms; Paclitaxel; Protein Binding; Structure-Activity Relationship; Tubulin Modulators
PubMed: 25434353
DOI: 10.2174/1568026614666141130095855 -
Journal of Thoracic Oncology : Official... Nov 2009
Topics: Antimitotic Agents; Humans; Lung Neoplasms; Mitosis
PubMed: 19861923
DOI: 10.1097/01.JTO.0000361756.09789.56 -
Pharmaceutical Biology Dec 2024Podophyllotoxin (PPT) derivatives, used in cancer therapy, require development toward enhanced efficacy and reduced toxicity.
CONTEXT
Podophyllotoxin (PPT) derivatives, used in cancer therapy, require development toward enhanced efficacy and reduced toxicity.
OBJECTIVE
This study synthesizes PPT derivatives to assess their anticancer activities.
MATERIALS AND METHODS
Compounds E1-E16 antiproliferative activity was tested against four human cancer cell lines (H446, MCF-7, HeLa, A549) and two normal cell lines (L02, BEAS-2B) using the CCK-8 assay. The effects of compound on A549 cell growth were evaluated through molecular docking, assays (flow cytometry, wound healing, Transwell, colony formation, Western blot), and tests in female BALB/c nude mice treated with (2 and 4 mg/kg). (4 mg/kg) significantly reduced xenograft tumor growth compared to the DMSO control group.
RESULTS
Among the 16 PPT derivatives tested for cytotoxicity, exhibited potent effects against A549 cells (IC: 0.35 ± 0.13 µM) and exceeded the reference drugs PPT and etoposide to inhibit the growth of xenograft tumours. -induced cell cycle arrest in the S and G2/M phases accelerated tubulin depolymerization and triggered apoptosis and mitochondrial depolarization while regulating the expression of apoptosis-related proteins and effectively inhibited cell migration and invasion, suggesting a potential to limit metastasis. Molecular docking showed binding of to tubulin at the colchicine site and to Akt, with a consequent down-regulation of PI3K/Akt pathway proteins.
DISCUSSION AND CONCLUSIONS
This research lays the groundwork for advancing cancer treatment through developing and using PPT derivatives. The encouraging results associated with call for extended research and clinical validation, leading to novel and more effective cancer therapies.
Topics: Mice; Animals; Humans; Female; Podophyllotoxin; Tubulin; Molecular Docking Simulation; Mice, Nude; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Drug Screening Assays, Antitumor; Antineoplastic Agents; Cell Proliferation; Cell Line, Tumor; Apoptosis; Tubulin Modulators
PubMed: 38393642
DOI: 10.1080/13880209.2024.2318350 -
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