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Chemical Communications (Cambridge,... Oct 2016An antimitotic cell penetrating octapeptide containing single Arg amino acid is discovered, which strongly binds with the exchangeable GTP/GDP binding site of tubulin,...
An antimitotic cell penetrating octapeptide containing single Arg amino acid is discovered, which strongly binds with the exchangeable GTP/GDP binding site of tubulin, inhibits tubulin polymerization, reduces kinesin driven microtubule motility, activates apoptotic and mitotic check point proteins, induces apoptotic death and significantly inhibits the multicellular tumor spheroid growth of HeLa cells.
Topics: Antimitotic Agents; Apoptosis; Binding Sites; Cell-Penetrating Peptides; Genes, cdc; HeLa Cells; Humans; Microtubules; Mitosis; Polymerization; Tubulin
PubMed: 27713939
DOI: 10.1039/c6cc05110c -
Current Medicinal Chemistry 2013Nitrogen-containing bioactive alkaloids of plant origin play a significant role in human health and medicine. Several semisynthetic antimitotic alkaloids are successful... (Review)
Review
Nitrogen-containing bioactive alkaloids of plant origin play a significant role in human health and medicine. Several semisynthetic antimitotic alkaloids are successful in anticancer drug development. Gloriosa superba biosynthesizes substantial quantities of colchicine, a bioactive molecule for gout treatment. Colchicine also has antimitotic activity, preventing growth of cancer cells by interacting with microtubules, which could lead to the design of better cancer therapeutics. Further, several colchicine semisynthetics are less toxic than colchicine. Research is being conducted on effective, less toxic colchicine semisynthetic formulations with potential drug delivery strategies directly targeting multiple solid cancers. This article reviews the dynamic state of anticancer drug development from colchicine semisynthetics and natural colchicine production and briefly discusses colchicine biosynthesis.
Topics: Antimitotic Agents; Colchicine; Drug Delivery Systems; Humans; Liliaceae; Nanomedicine; Neoplasms; Tubulin Modulators
PubMed: 23210778
DOI: No ID Found -
Hand Clinics Aug 2018Clinicians struggle with limited efficacy and durability of standard treatments when treating patients with Dupuytren disease diathesis. Alternative treatments such as... (Review)
Review
Clinicians struggle with limited efficacy and durability of standard treatments when treating patients with Dupuytren disease diathesis. Alternative treatments such as low-dose radiation therapy in early phase of disease, supplemental pharmacotherapy with anti-inflammatory and/or anti-mitotic drugs, as well as other pharmacologic targets, and more aggressive surgery such as dermofasciectomy all have been reported with variable success or with serious side effects that hamper their standard use. This article gives an overview of the available literature.
Topics: Acellular Dermis; Anti-Inflammatory Agents; Antimitotic Agents; Dupuytren Contracture; Fasciotomy; Humans; Radiotherapy; Secondary Prevention; Surgical Flaps
PubMed: 30012296
DOI: 10.1016/j.hcl.2018.03.005 -
Advances in Experimental Medicine and... 2017Mitosis is one of the most fundamental processes of life by which a mammalian cell divides into two daughter cells. Mitosis has been an attractive target for anticancer... (Review)
Review
Mitosis is one of the most fundamental processes of life by which a mammalian cell divides into two daughter cells. Mitosis has been an attractive target for anticancer therapies since fast proliferation was identified as one of the hallmarks of cancer cells. Despite efforts into developing specific inhibitors for mitotic kinases and kinesins, very few drugs have shown the efficiency of microtubule targeting-agents in cancer cells with paclitaxel being the most successful. A deeper translational research accompanying clinical trials of anti-mitotic drugs will help in identifying potent biomarkers predictive for response. Here, we review the current knowledge of mitosis targeting agents that have been tested so far in the clinics.
Topics: Animals; Antimitotic Agents; Cell Proliferation; Drug Discovery; Humans; Mitosis; Molecular Targeted Therapy; Neoplasms; Signal Transduction
PubMed: 28600785
DOI: 10.1007/978-3-319-57127-0_6 -
Current Opinion in Pharmacology Aug 2013Several mitotic kinases and kinesins are currently considered as cancer targets based on their critical role during the cell division cycle and their significant level... (Review)
Review
Several mitotic kinases and kinesins are currently considered as cancer targets based on their critical role during the cell division cycle and their significant level of expression in human tumors. Yet, their use is limited by the lack of selectivity against tumor cells, the low percentage of mitotic cells in many human tumors, and dose-limiting side-effects. As a consequence, initial clinical trials have shown limited responses. Despite these drawbacks, inhibiting mitosis is a promising strategy that deserves further development. Future advances will benefit from more specific inhibitors with better pharmacodynamic properties, a clear physiological characterization and cell-type-specific requirements of old and new mitotic targets, and rational strategies based on synthetic lethal interactions to improve selectivity against tumor cells.
Topics: Animals; Antimitotic Agents; Antineoplastic Combined Chemotherapy Protocols; Humans; Kinesins; Mitosis; Neoplasms; Protein Kinase Inhibitors; Protein Kinases
PubMed: 23583638
DOI: 10.1016/j.coph.2013.03.011 -
Journal of Cellular Biochemistry Oct 2010Mitosis is the key event of the cell cycle during which the sister chromatids are segregated onto two daughter cells. It is well established that abrogation of the...
Mitosis is the key event of the cell cycle during which the sister chromatids are segregated onto two daughter cells. It is well established that abrogation of the normal mitotic progression is a highly efficient concept for anti-cancer treatment. In fact, various drugs that target microtubules and thus interfere with the function of the mitotic spindle are in clinical use for the treatment of various human malignancies for many years. However, since microtubule inhibitors not only target proliferating cells severe side effects limit their use. Therefore, the identification of novel mitotic drug targets other than microtubules have gained recently much attention. This review will summarize the latest developments on the identification and clinical evaluation of novel mitotic drug targets and will introduce novel concepts for chemotherapy that are based on recent progress in our understanding how mitotic progression is regulated and how anti-mitotic drugs induce tumor cell death.
Topics: Antimitotic Agents; Antineoplastic Agents; Drug Delivery Systems; Humans; Mitosis; Neoplasms
PubMed: 20518069
DOI: 10.1002/jcb.22721 -
Bioorganic & Medicinal Chemistry Letters Dec 2020Indibulin (D-24851) derivatives with bisphosphonate fragment connected to the N1 atom of imidazole ring were synthesized by alkylation of (indolyl-3)methylglyoxylates...
Indibulin (D-24851) derivatives with bisphosphonate fragment connected to the N1 atom of imidazole ring were synthesized by alkylation of (indolyl-3)methylglyoxylates with ethylenebisphosphonate. Biological evaluation of targeted compounds 4a-d using the phenotypic sea urchin embryo assay provided evidence that replacing of p-chlorobenzene ring in indibulin by bisphosphonate group did not eliminate antimitotic microtubule destabilizing activity. The most active molecule, tetraacid 5a, at physiological pH formed tetrasodium salt 6a with aqueous solubility value of at least 10 mg/mL. Molecule 5a was more potent in the sea urchin embryo assay than the parent indibulin. This compound also exhibited pronounced cytotoxicity against A549 lung carcinoma and A375 melanoma cell lines.
Topics: Acetamides; Animals; Antimitotic Agents; Cell Line, Tumor; Diphosphonates; Drug Screening Assays, Antitumor; Embryo, Nonmammalian; Humans; Indoles; Sea Urchins; Solubility
PubMed: 33132173
DOI: 10.1016/j.bmcl.2020.127635 -
Cell Reports Apr 2017Antimitotic agents, including Taxol, disrupt microtubule dynamics and cause a protracted mitotic arrest and subsequent cell death. Despite the broad utility of these...
Antimitotic agents, including Taxol, disrupt microtubule dynamics and cause a protracted mitotic arrest and subsequent cell death. Despite the broad utility of these drugs in breast cancer and other tumor types, clinical response remains variable. Tumor-associated macrophages (TAMs) suppress the duration of Taxol-induced mitotic arrest in breast cancer cells and promote earlier mitotic slippage. This correlates with a decrease in the phosphorylated form of histone H2AX (γH2AX), decreased p53 activation, and reduced cancer cell death in interphase. TAMs promote cancer cell viability following mitotic slippage in a manner sensitive to MAPK/ERK kinase (MEK) inhibition. Acute depletion of major histocompatibility complex class II low (MHCII) TAMs increased Taxol-induced DNA damage and apoptosis in cancer cells, leading to greater efficacy in intervention trials. MEK inhibition blocked the protective capacity of TAMs and phenocopied the effects of TAM depletion on Taxol treatment. TAMs suppress the cytotoxic effects of Taxol, in part through cell non-autonomous modulation of mitotic arrest in cancer cells, and targeting TAM-cancer cell interactions potentiates Taxol efficacy.
Topics: Animals; Antimitotic Agents; Apoptosis; Benzothiazoles; Breast Neoplasms; Cell Survival; DNA Damage; Endothelial Cells; Female; Histones; Humans; Macrophages; Major Histocompatibility Complex; Mice; Mice, Transgenic; Mitogen-Activated Protein Kinase Kinases; Mitosis; Paclitaxel; Picolinic Acids; Tumor Cells, Cultured; Tumor Suppressor Protein p53
PubMed: 28380350
DOI: 10.1016/j.celrep.2017.03.038 -
Endocrine-related Cancer Sep 2017Antimicrotubule agents are commonly utilised as front-line therapies against several malignancies, either by themselves or as combination therapies. Cell-based studies... (Review)
Review
Antimicrotubule agents are commonly utilised as front-line therapies against several malignancies, either by themselves or as combination therapies. Cell-based studies have pinpointed the anti-proliferative basis of action to be a consequence of perturbation of microtubule dynamics leading to sustained activation of the spindle assembly checkpoint, prolonged mitotic arrest and mitotic cell death. However, depending on the biological context and cell type, cells may take an alternative route besides mitotic cell death via a process known as mitotic slippage. Here, mitotically arrested cells 'slip' to the next interphase without undergoing proper chromosome segregation and cytokinesis. These post-slippage cells in turn have two main cell fates, either cell death or a G1 arrest ensuing in senescence. In this review, we take a look at the factors determining mitotic cell death vs mitotic slippage, post-slippage cell fates and accompanying features, and their consequences for antimicrotubule drug treatment outcomes.
Topics: Animals; Antimitotic Agents; Cell Death; Cellular Senescence; Drug Resistance, Neoplasm; Humans; Microtubules; Mitosis; Neoplasms; Polyploidy
PubMed: 28684541
DOI: 10.1530/ERC-17-0147 -
Anti-cancer Agents in Medicinal... Mar 2012The Vinca alkaloids are a group of widely used anticancer drugs, originally extracted from the Madagascar periwinkle, that disrupt microtubule dynamics in mammalian...
The Vinca alkaloids are a group of widely used anticancer drugs, originally extracted from the Madagascar periwinkle, that disrupt microtubule dynamics in mammalian cells by interfering with proper assembly of α,β-tubulin heterodimers. They favor curved tubulin assemblies that destabilize microtubules and induce formation of spiral aggregates. Their binding energy profiles have been characterized by means of sedimentation velocity assays and the binding site of vinblastine at the interface between two tubulin dimers (α1β1 � α2β2) has been ascertained by X-ray crystallographic studies on a complex of tubulin with the stathmin-like domain of protein RB3, albeit at relatively low resolution. Here we use molecular modeling and simulation techniques to build, refine and perform a comparative analysis of the three-dimensional complexes of vinblastine, vincristine, vinorelbine and vinflunine with a β1α2-tubulin interface in explicit water to rationalize the binding affinity differences in structural and energetic terms. Our results shed some more light into the binding determinants and the structure-activity relationships of these clinically useful agents.
Topics: Amino Acid Sequence; Antimitotic Agents; Antineoplastic Agents, Phytogenic; Binding Sites; Molecular Dynamics Simulation; Molecular Sequence Data; Protein Structure, Tertiary; Sequence Homology, Amino Acid; Structure-Activity Relationship; Tubulin; Vinca Alkaloids
PubMed: 22044006
DOI: 10.2174/187152012800228841