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Molecules (Basel, Switzerland) Dec 2020Microtubule-targeting agents (MTAs) remain a gold standard for the treatment of several cancer types. By interfering with microtubules dynamic, MTAs induce a mitotic...
Microtubule-targeting agents (MTAs) remain a gold standard for the treatment of several cancer types. By interfering with microtubules dynamic, MTAs induce a mitotic arrest followed by cell death. This antimitotic activity of MTAs is dependent on the spindle assembly checkpoint (SAC), which monitors the integrity of the mitotic spindle and proper chromosome attachments to microtubules in order to ensure accurate chromosome segregation and timely anaphase onset. However, the cytotoxic activity of MTAs is restrained by drug resistance and/or toxicities, and had motivated the search for new compounds and/or alternative therapeutic strategies. Here, we describe the synthesis and mechanism of action of the xanthone derivative pyranoxanthone that exhibits a potent anti-growth activity against cancer cells. We found that cancer cells treated with the pyranoxanthone exhibited persistent defects in chromosome congression during mitosis that were not corrected over time, which induced a prolonged SAC-dependent mitotic arrest followed by massive apoptosis. Importantly, pyranoxanthone was able to potentiate apoptosis of cancer cells treated with nanomolar concentrations of paclitaxel. Our data identified the potential of the pyranoxanthone as a new potent antimitotic with promising antitumor potential, either alone or in combination regimens.
Topics: Antimitotic Agents; Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Chemistry Techniques, Synthetic; Chromosome Aberrations; Fluorescent Antibody Technique; Humans; M Phase Cell Cycle Checkpoints; Microtubules; Mitosis; Molecular Structure; Paclitaxel; Pyrans; Xanthones
PubMed: 33322077
DOI: 10.3390/molecules25245845 -
Expert Opinion on Investigational Drugs Jan 2020: Kinesin spindle protein (KSP) is indispensable for the proper separation of spindle poles during mitosis. Importantly, this protein is expressed only in cells... (Review)
Review
: Kinesin spindle protein (KSP) is indispensable for the proper separation of spindle poles during mitosis. Importantly, this protein is expressed only in cells undergoing cell division and hence represents an appealing target for the treatment of cancer. Many KSP inhibitors have demonstrated a strong antitumoral effect , however, they have exhibited only limited activity in clinical trials. By contrast, the KSP inhibitor filanesib has demonstrated clinical efficacy in patients with multiple myeloma (MM).: This article provides a comprehensive overview about the progress to date in the preclinical and clinical development of filanesib for the treatment of cancer, and particularly, MM.: Responses observed with filanesib alone or in combination with dexamethasone were encouraging in MM. However, the subsequent appearance of highly effective novel agents such as monoclonal antibodies, has hindered the development of agents such as filanesib that exhibit a more limited activity. Nevertheless, filanesib has shown interesting results for some patients when combined with carfilzomib and pomalidomide. Most importantly, the availability of a biomarker of response such as alpha 1-acid glycoprotein (AAG), could be key to the identification of patients that could benefit most from these combinations.
Topics: Animals; Antimitotic Agents; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Drug Development; Humans; Kinesins; Multiple Myeloma; Thiadiazoles
PubMed: 31815551
DOI: 10.1080/13543784.2020.1703179 -
Bioorganic Chemistry Mar 2019A library of 1-benzyl-N-(2-(phenylamino)pyridin-3-yl)-1H-1,2,3-triazole-4-carboxamides (7a-al) have been designed, synthesized and screened for their anti-proliferative...
A library of 1-benzyl-N-(2-(phenylamino)pyridin-3-yl)-1H-1,2,3-triazole-4-carboxamides (7a-al) have been designed, synthesized and screened for their anti-proliferative activity against some selected human cancer cell lines namely DU-145, A-549, MCF-7 and HeLa. Most of them have shown promising cytotoxicity against lung cancer cell line (A549), amongst them 7f was found to be the most potent anti-proliferative congener. Furthermore, 7f exhibited comparable tubulin polymerization inhibition (IC value 2.04 µM) to the standard E7010 (IC value 2.15 µM). Moreover, flow cytometric analysis revealed that this compound induced apoptosis via cell cycle arrest at G/M phase in A549 cells. Induction of apoptosis was further observed by examining the mitochondrial membrane potential and was also confirmed by Hoechst staining as well as Annexin V-FITC assays. Furthermore, molecular docking studies indicated that compound 7f binds to the colchicine binding site of the β-tubulin. Thus, 7f exhibits anti-proliferative properties by inhibiting the tubulin polymerization through the binding at the colchicine active site and by induction of apoptosis.
Topics: Aminopyridines; Animals; Antimitotic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Drug Design; Drug Screening Assays, Antitumor; G2 Phase Cell Cycle Checkpoints; Humans; Membrane Potential, Mitochondrial; Molecular Docking Simulation; Molecular Structure; Polymerization; Protein Binding; Rats; Sheep, Domestic; Structure-Activity Relationship; Triazoles; Tubulin; Tubulin Modulators
PubMed: 30472555
DOI: 10.1016/j.bioorg.2018.11.002 -
Trends in Cell Biology Oct 2018Microtubule-targeting agents (MTAs) such as paclitaxel and the vinca alkaloids are among the most important medical weapons available to combat cancer. MTAs interfere... (Review)
Review
Microtubule-targeting agents (MTAs) such as paclitaxel and the vinca alkaloids are among the most important medical weapons available to combat cancer. MTAs interfere with intracellular transport, inhibit eukaryotic cell proliferation, and promote cell death by suppressing microtubule dynamics. Recent advances in the structural analysis of MTAs have enabled the extensive characterization of their interactions with microtubules and their building block tubulin. We review here our current knowledge on the molecular mechanisms used by MTAs to hijack the microtubule cytoskeleton, and discuss dual inhibitors that target both kinases and microtubules. We further formulate some outstanding questions related to MTA structural biology and present possible routes for future investigations of this fascinating class of antimitotic agents.
Topics: Antimitotic Agents; Antineoplastic Agents, Phytogenic; Humans; Microtubules; Mitosis; Paclitaxel; Phosphotransferases
PubMed: 29871823
DOI: 10.1016/j.tcb.2018.05.001 -
Bioorganic & Medicinal Chemistry Apr 2016A series of phenstatin/isocombretastatin-oxindole conjugates was synthesized and tested for their cytotoxic activity against five human cancer cells such as prostate...
A series of phenstatin/isocombretastatin-oxindole conjugates was synthesized and tested for their cytotoxic activity against five human cancer cells such as prostate (DU-145), lung (A549), colon (HT-29), breast (MCF-7), liver (HepG2) cancer cells with IC50 values ranging from 0.049 to 38.90 μM. Amongst them, two conjugates (5c and 5d) showed broad spectrum of antiproliferative efficacy on lung cancer cells with an IC50 value of 79 nM and 93 nM, respectively, whereas on colon cancer cells with an IC50 values 45 nM and 49 nM, respectively. In addition, cell cycle assay revealed that these conjugates (5c and 5d) arrest at the G2/M phase and leads to apoptotic cell death which was confirmed by Annexin V-FITC and mitochondrial membrane depolarization. Further, the tubulin polymerization assay analysis results suggest that these conjugates particularly 5c and 5d exhibit significant inhibitory effect on the tubulin assembly with an IC50 value of 1.23 μM and 1.01 μM, respectively. Molecular docking studies indicated that these compounds (5c and 5d) occupy the colchicine binding site of the tubulin.
Topics: Antimitotic Agents; Antineoplastic Agents; Apoptosis; Benzophenones; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Humans; Indoles; Molecular Docking Simulation; Molecular Structure; Organophosphates; Oxindoles; Stilbenes; Structure-Activity Relationship
PubMed: 26970659
DOI: 10.1016/j.bmc.2016.02.047 -
Molecular Biology of the Cell Jan 2012Cytotoxic cancer chemotherapy drugs are believed to gain selectivity by targeting cells that proliferate rapidly. However, the proliferation rate is low in many...
Cytotoxic cancer chemotherapy drugs are believed to gain selectivity by targeting cells that proliferate rapidly. However, the proliferation rate is low in many chemosensitive human cancers, and it is not clear how a drug that only kills dividing cells could promote tumor regression. Four potential solutions to this "proliferation rate paradox" are discussed for the microtubule-stabilizing drug paclitaxel: drug retention in tumors, killing of quiescent cells, targeting of noncancer cells in the tumor, and bystander effects. Testing these potential mechanisms of drug action will facilitate rational improvement of antimitotic chemotherapy and perhaps cytotoxic chemotherapy more generally.
Topics: Animals; Antimitotic Agents; Bystander Effect; Cell Cycle; Cell Death; Cell Line, Tumor; Cell Proliferation; Humans; Neoplasms
PubMed: 22210845
DOI: 10.1091/mbc.E10-04-0335 -
Journal of Medicinal Chemistry Oct 2011The synthesis and biological activity of oleylN-acetyl-α- and β-d-glucosaminides (1 and 2, respectively) and their thioglycosyl analogues (3 and 4, respectively) are...
The synthesis and biological activity of oleylN-acetyl-α- and β-d-glucosaminides (1 and 2, respectively) and their thioglycosyl analogues (3 and 4, respectively) are reported. The compounds exhibited antimitotic activity on rat glioma (C6) and human lung carcinoma (A549) cell cultures in the micromolar range. Analysis of cell extracts using ultra performance liquid chromatography-mass spectrometry showed that the synthetic glycosides produce alterations in glycosphingolipid metabolism, with variable effect on the level of glucosylceramide depending on the configuration of the antimitotic used. In vivo experiments in nude mice bearing an implanted C6 glioma showed that the α-thioglycoside 3 reduced tumor volume, while the O-glycosyl derivative was inactive, highlighting the importance of using enzyme resistant glycosides.
Topics: Animals; Antimitotic Agents; Cell Line, Tumor; Drug Screening Assays, Antitumor; Glycolipids; Humans; Hydrolysis; Mice; Mice, Nude; Neoplasm Transplantation; Rats; Structure-Activity Relationship; Thioglucosides; Thioglycosides; Transplantation, Heterologous; Tumor Burden; beta-N-Acetylhexosaminidases
PubMed: 21866909
DOI: 10.1021/jm200961q -
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 -
Bioorganic & Medicinal Chemistry Letters Jan 2015Two substituted biaryl analogues of colchicine and combretastatin A4, readily available through a one-step, protecting group free Suzuki-Miyaura reaction were discovered...
Two substituted biaryl analogues of colchicine and combretastatin A4, readily available through a one-step, protecting group free Suzuki-Miyaura reaction were discovered to exhibit anticancer activity while simultaneously being of low cytotoxicity to noncancerous cell lines. The compounds were shown to initiate apoptosis selectively via a mechanism involving inhibition of tubulin polymerization.
Topics: Antimitotic Agents; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Colchicine; Dose-Response Relationship, Drug; Humans; Stilbenes; Structure-Activity Relationship
PubMed: 25466200
DOI: 10.1016/j.bmcl.2014.10.090 -
Biochimica Et Biophysica Acta Jul 1953
Topics: Amidohydrolases; Animals; Antimitotic Agents; Arginase; Mitosis; Poisons; Research Design; Sarcoma, Experimental; Tissue Culture Techniques
PubMed: 13093745
DOI: 10.1016/0006-3002(53)90058-4