Antimitotic Properties Research Articles

Tumor treating fields: a novel and effective therapy for glioblastoma: mechanism, efficacy, safety and future perspectives.

Tumor treating fields (TTF, Optune®), one of the low-intensity alternating electric fields, have been demonstrated to disrupt mitosis and inhibit tumor growth with antimitotic properties in a variety of tumor types. The Food and Drug Administration (FDA) of the United States approved TTF for recurrent GBM and newly diagnosed GBM in 2011 and 2015, respectively. A systematic review was conducted regarding the relevant studies published between January 1, 2000, and May 31, 2017 in PubMed database. The search term included "Tumor Treating Fields", "Optune", "TTF", "Novocure", and "GBM". This review summarizes the mechanism of action, efficacy, and adverse events based on pre-clinical studies and clinical trials for TTF in GBM. Pre-clinical studies showed that TTF could inhibit tumor growth in vitro and in vivo by disrupting mitosis, inducing cell cycle arrest and apoptosis. Two randomized phase III trials evaluated the efficacy and safety of TTF in GBM patients. It was revealed that the combination of TTF and standard chemotherapy (temozolomide) prolonged the progression-free survival (PFS) and overall survival (OS) without systemic safety issues in newly diagnosed GBM (EF-14 trial). For recurrent GBM, the efficacy of TTF monotherapy was shown to be equivalent in PFS and OS without systemic adverse events when compared to the control group that received best physicians-chosen chemotherapies (EF-11 trial). The advantages of TTF in GBM treatment, including non-invasive antitumor effect, superior therapeutic benefit in combination with chemotherapy, and minimal systematic toxicity, have been demonstrated in pre-clinical data and randomized phased III clinical trials. Future investigations will be needed to explore combinations of chemotherapy, radiation therapy, targeted therapy, as well as immunotherapy with this novel anti-tumor treatment modality to achieve additive or synergistic therapeutic benefit for GBM and other solid tumors.

Pyridine-pyrimidine amides that prevent HGF-induced epithelial scattering by two distinct mechanisms

Stimulation of cultured epithelial cells with scatter factor/hepatocyte growth factor (HGF) results in individual cells detaching and assuming a migratory and invasive phenotype. Epithelial scattering recapitulates cancer progression and studies have implicated HGF signaling as a driver of cancer metastasis. Inhibitors of HGF signaling have been proposed to act as anti-cancer agents. We previously screened a small molecule library for compounds that block HGF-induced epithelial scattering. Most hits identified in this screen exhibit anti-mitotic properties. Here we assess the biological mechanism of a compound that blocks HGF-induced scattering with limited anti-mitotic activity. Analogs of this compound have one of two distinct activities: inhibiting either cell migration or cell proliferation with cell cycle arrest in G2/M. Each activity bears unique structure–activity relationships. The mechanism of action of anti-mitotic compounds is by inhibition of microtubule polymerization; these compounds entropically and enthalpically bind tubulin in the colchicine binding site, generating a conformational change in the tubulin dimer.

Synthesis and antimitotic properties of ortho-substituted polymethoxydiarylazolopyrimidines

Synthesis and antimitotic properties of ortho-substituted polymethoxydiarylazolopyrimidines

Xanthium strumarium extract inhibits mammalian cell proliferation through mitotic spindle disruption mediated by xanthatin

Ethnopharmacological relevanceXanthium strumarium L. is a member of the Asteraceae family popularly used with multiple therapeutic purposes. Whole extracts of this plant have shown anti-mitotic activity in vitro suggesting that some components could induce mitotic arrest in proliferating cells. Aim of the sudyAim of the present work was to characterize the anti-mitotic properties of the X. strumarium whole extract and to isolate and purify active molecule(s). Materials and methodsThe capacity of the whole extract to inhibit mitotic progression in mammalian cultured cells was investigated to identify its anti-mitotic activity. Isolation of active component(s) was performed using a bioassay-guided multistep separation procedure in which whole extract was submitted to a progressive process of fractionation and fractions were challenged for their anti-mitotic activity. ResultsOur results show for the first time that X. strumarium whole extract inhibits assembly of the mitotic spindle and spindle-pole separation, thereby heavily affecting mitosis, impairing the metaphase to anaphase transition and inducing apoptosis. The purification procedure led to a fraction with an anti-mitotic activity comparable to that of the whole extract. Chemical analysis of this fraction showed that its major component was xanthatin. ConclusionsThe present work shows a new activity of X. strumarium extract, i.e. the alteration of the mitotic apparatus in cultured cells that may be responsible for the anti-proliferative activity of the extract. Anti-mitotic activity is shown to be mainly exerted by xanthatin.

Fatostatin Inhibits Cancer Cell Proliferation by Affecting Mitotic Microtubule Spindle Assembly and Cell Division

The sterol regulatory element-binding protein (SREBP) transcription factors have become attractive targets for pharmacological inhibition in the treatment of metabolic diseases and cancer. SREBPs are critical for the production and metabolism of lipids and cholesterol, which are essential for cellular homeostasis and cell proliferation. Fatostatin was recently discovered as a specific inhibitor of SREBP cleavage-activating protein (SCAP), which is required for SREBP activation. Fatostatin possesses antitumor properties including the inhibition of cancer cell proliferation, invasion, and migration, and it arrests cancer cells in G2/M phase. Although Fatostatin has been viewed as an antitumor agent due to its inhibition of SREBP and its effect on lipid metabolism, we show that Fatostatin's anticancer properties can also be attributed to its inhibition of cell division. We analyzed the effect of SREBP activity inhibitors including Fatostatin, PF-429242, and Betulin on the cell cycle and determined that only Fatostatin possessed antimitotic properties. Fatostatin inhibited tubulin polymerization, arrested cells in mitosis, activated the spindle assembly checkpoint, and triggered mitotic catastrophe and reduced cell viability. Thus Fatostatin's ability to inhibit SREBP activity and cell division could prove beneficial in treating aggressive types of cancers such as glioblastomas that have elevated lipid metabolism and fast proliferation rates and often develop resistance to current anticancer therapies.

Colchicine may assist in reducing granulation tissue in junctional epidermolysis bullosa.

Epidermolysis bullosa (EB) is a rare, inherited blistering genodermatosis. Patients with junctional EB (JEB) due to LAMB3 mutations have widespread blisters and erosions of skin, mucosae, and nails, creating significant physical, emotional, and psychosocial burdens. Here we report the use of colchicine for ameliorating hypergranulating wounds in a 41-year-old female with JEB generalized intermediate. Her skin wounds and granulation tissue gradually exacerbated under silicone dressings such that she became profoundly anemic. Subsequently, she was commenced on colchicine 500 μg daily on the basis that it may inhibit cell proliferation and be anti-inflammatory. After a 6-month trial of colchicine, she had an objective and subjective improvement in her validated EB Disease Activity and Scarring Index activity and damage scores and Quality Of Life in EB score with less skin erosions, granulation tissue, and erythema. In addition, her anemia resolved. She denied any gastrointestinal side effects. The exact mechanism of colchicine in assisting reduction of the blistering, erosions, and granulation in JEB is unclear, but the anti-inflammatory and antimitotic properties of colchicine may be partially responsible for this process.

Nanodiamonds coupled with 5,7-dimethoxycoumarin, a plant bioactive metabolite, interfere with the mitotic process in B16F10 cells altering the actin organization.

For the first time, we coupled reduced detonation nanodiamonds (NDs) with a plant secondary metabolite, citropten (5,7-dimethoxycoumarin), and demonstrated how this complex was able to reduce B16F10 tumor cell growth more effectively than treatment with the pure molecule. These results encouraged us to find out the specific mechanism underlying this phenomenon. Internalization kinetics and quantification of citropten in cells after treatment with its pure or ND-conjugated form were measured, and it was revealed that the coupling between NDs and citropten was essential for the biological properties of the complex. We showed that the adduct was not able to induce apoptosis, senescence, or differentiation, but it determined cell cycle arrest, morphological changes, and alteration of mRNA levels of the cytoskeletal-related genes. The identification of metaphasic nuclei and irregular disposition of β-actin in the cell cytoplasm supported the hypothesis that citropten conjugated with NDs showed antimitotic properties in B16F10 cells. This work can be considered a pioneering piece of research that could promote and support the biomedical use of plant drug-functionalized NDs in cancer therapy.

Evaluation of Bioactivity and Preliminary Phytochemical Investigation of Herbal Plants Against Ampicillin Resistant Bacteria

Presently, natural products are extensively used as substitute of synthetic drugs because of natural and environment friendly antimicrobial actions due to presence of bioactive compounds. These bioactive compounds are found extensively in herbs. In this study, bioactivity and phytochemical study of crude extracts of Ocimum basilicum, Thymus vulgaris, Rosmarinus officinalis and Origanum vulgare against ampicillin resistant bacterial strains isolated from fruits and vegetables eaten as raw, was investigated. Bacterial strains were isolated from the surface of selected washed fruits and vegetables by serial dilution method. Three morphologically different strains (A, P and L) were selected on the basis of resistance to ampicillin (150ug/ml). 16s rRNA sequencing revealed that bacterial strains A, P and L belong to Pseudomonas aeruginosa strain A, Pseudomonas aeruginosa strain P and Rhodobacter sphaeroides, respectively. Phytochemical screening showed presence of different chemical compounds such as alkaloids, tannins, saponins, phlobotannins, quinones, coumarin and flavonoids. Occurrence of saponins and flavonoids in the extract was further confirmed by thin layer chromatography (TLC). Ocimum basilicum, Rosmarinus officinalis and Origanum vulgare extracts caused inhibition of the isolated ampicillin resistant organisms (Pseudomonas aeruginosa) but effect of Thymus vulgaris was more pronounced. Anti-mitotic study revealed the ability of these extracts to reduce dividing cells by the anti-mitotic properties and this is helpful in inhibition of the development of cancer cells. Therefore, these plants can be used to discover natural products that will aid in more effective developments of new drug research activities.

Tumor treating fields: a new standard treatment for glioblastoma?

Tumor treating fields (TTFields), an external therapeutic device with antimitotic properties, is a Food and Drug Administration approved treatment for recurrent glioblastoma (GBM) that has been reported to be efficacious in newly diagnosed GBM as well. Preclinical data show that TTFields is an antimitotic agent that additionally augments response to alkylator-based chemotherapy. In a single study, nearly 15% of recurrent GBM treated with TTFields alone display durable responses. Responses may be delayed, sometimes after an initial progression, and are highly correlated to treatment compliance and to survival. In newly diagnosed GBM, a preplanned interim analysis of the phase III randomized trial (standard of care with or without TTFields) showed a statistically significant effect of TTFields resulting in a net gain of 3 months in both progression-free and overall survival. TTFields is a novel noninvasive therapeutic option for recurrent GBM. The role of TTFields in newly diagnosed GBM will be adjudicated pending publication of the final results of the randomized EF-14 trial. If these results are compelling, this may result in accelerated approval and potentially a new standard of care for newly diagnosed GBM.

ChemInform Abstract: Synthesis of a Novel Polycyclic Ring Scaffold with Antimitotic Properties via a Selective Domino Heck—Suzuki Reaction.

Abstract13 Title compounds of type (III) are prepared and screened for their antimitotic properties.

Synthesis of a novel polycyclic ring scaffold with antimitotic properties via a selective domino Heck-Suzuki reaction.

The synthesis of a previously undescribed sp3-rich 6-5-5-6 tetracyclic ring scaffold using a palladium catalysed domino Heck-Suzuki reaction is reported. This reaction is high-yielding, selective for the domino process over the direct Suzuki reaction and tolerant towards a variety of boronic acids. The novel scaffold can also be accessed via domino Heck-Stille and radical cyclisations. Compounds based around this scaffold were found to be effective antimitotic agents in a human cancer cell line. Detailed phenotypic profiling showed that the compounds affected the congression of chromosomes to give mitotic arrest and apoptotic cell death. Thus, a novel structural class of antimitotic agents that does not disrupt the tubulin network has been identified.

In vitro and in vivo anti-glioma activity of a chalcone-quinoxaline hybrid.

Chalcones are important compounds that exhibit multiple biological activities, including anti-inflammatory, antimitotic and antibacterial properties. In the present study, we have analyzed the potential anti-cancer activity of a chalcone named N9 (a hybrid chalcone-quinoxaline compound) using in vitro and in vivo experimental glioma models. Here, we report N9-induced inhibition of cell proliferation and also N9-induced cell death in a concentration-dependent manner in U87-MG glioma cells. These effects of N9 appear to be associated with its ability to inhibit the expression of cell cycle-associated proteins, and also the augmentation in the expression of the p21 (p21/Cip1) protein, a cyclin-dependent kinase inhibitor. Additionally, N9 also potentiates the production of the pro-apoptotic markers Bax and p53 via inhibition of MDM2. Moreover, our results show that N9 also significantly enhanced apoptosis of U87-MG cells with disruption of mitochondrial membrane potential, generation of ROS and caspase-9 activation. In vivo experiments carried out in a murine xenograft model of U87-MG revealed that N9 produced a significant reduction of tumors volume when compared to vehicle treated mice. Collectively, data demonstrate that N9 possess in vitro and in vivo anti-cancer activity, an effect that seems to involve the induction of p53 and p21 proteins, as well as, the activation of mitochondrial apoptosis pathway associated with the inhibition of protein MDM2. Overall, this study suggests N9 is affecting a variety of intracellular pathways related to tumor apoptosis. Perhaps N9 or derivate molecules could represent new potential drugs for cancer therapeutics.

Ragged Robin (Lychnis flos-cuculi) - a plant with potential medicinal value

Lychnis flos-cuculi L., Caryophyllaceae, contains a number of active compounds belonging to several chemical groups. Previous studies have led to the identification of phytoecdysteroids, triterpenoids saponins, volatile compounds, fatty acid derivatives, phenolic acids and flavonoids. Research on pharmacological activity showed that plant extracts inhibited the growth of bacteria and fungi. The antimitotic properties of preparations from the herb L. flos-cuculi were also reported. The phytochemical analyses demonstrated that this taxon contains pharmaceutically promising compounds, but more phytochemical and pharmacological studies of L. flos-cuculi are needed for further information regarding this plant. This review summarizes reports regarding chemical composition and biological activity of L. flos-cuculi as well as several cognate species, which pose opportunities related to in vitro propagation and cell and tissue cultures. In vitro-regen-erated plantlets could be a good source of genetically uniform plant material for future research.

Abstract 757: ET-D5, first-in-class synthetic selective Protein Phosphatase 1 (PP1) inhibitor with anti-proliferative and anti-vascular activity

Abstract In this work we describe ET-D5, a synthetic small molecule serine-threonine protein phosphatase inhibitor with proven in vivo anti-mitotic and anti-vascular properties. The potential anti-cancer properties of serine-threonine protein phosphatase inhibitors have been identified since ancient times (extract from blister beetle mylabris was used in China for cancer treatment as early as in 1264), and several, mostly natural, inhibitors were evaluated in clinical trials. Their development was, however, discontinued due to the toxic effects of these non-selective (PP2A>>PP1) serine-threonine protein phosphatase inhibitors. ET-D5 is a remarkably specific (PP1 versus PP2A) inhibitor with potent anti-mitotic and anti-vascular activities. In vitro, ET-D5 display high efficacy against a wide range of human cancer cells (GI50 values determined were in low nM range for certain cell lines). In addition, ET-D5 disrupts the in vitro preformed capillary tubes (endothelial cells HMEC-1). In vivo experiments confirmed these activities in numerous animal models of human cancer, such as cancer of lung, brain, thyroid, kidney and ovaries. ET-D5 presents interesting pharmacological properties, good toxicology profile and is also active when administered per os. Contrary to many vascular-disrupting agents (VDA) which target tubulin, ET-D5 exerts its activity by selectively inhibiting in vivo protein-phosphatase I (PP1). We confirmed this activity in classical pharmacodynamics experiments, showing PP1 inhibition in xenografted tumors after oral administration of ET-D5. Based on all these results, ET-D5 is scheduled to enter clinical trials in early 2015. Citation Format: Aurelie Juhem, Delphine Lecercle, Julie Deverchère, Arnaud Gazel, Jean-Claude Florent, Andrei Popov. ET-D5, first-in-class synthetic selective Protein Phosphatase 1 (PP1) inhibitor with anti-proliferative and anti-vascular activity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 757. doi:10.1158/1538-7445.AM2014-757

Antimitotic effect of Selol and sodium selenate (IV) onAlliumtest cells

Selol is a mixture of selenitetriglycerides, obtained by esterification of pre-oxidated triglycerides from sunflower oil with selenous acid. Investigations have been carried out on the anticancer use of Selol and its antimitotic properties. The aim of our work was to compare the effect of two compounds (an organic and an inorganic one) containing selenium with oxidation number at +4: Selol and sodium selenate (IV), on plant cells of Allium test. Structural changes in cells, their mitotic activity and proportions of mitotic phases were subject to experimental analysis. Incubation in both selenium compounds led to changes in structure of chromosomes, consisting in their strong condensation and contraction (cc chromosomes), accompanied by gradual reduction or complete inhibition of cell division. High concentrations of Selol led to strong condensation of chromatin in interphase cells, while cells treated with high concentrations of sodium selenate (IV) displayed typical “pseudoapoptotic” bodies and totally f...

Novel colchicine-site binders with a cyclohexanedione scaffold identified through a ligand-based virtual screening approach.

Vascular disrupting agents (VDAs) constitute an innovative anticancer therapy that targets the tumor endothelium, leading to tumor necrosis. Our approach for the identification of new VDAs has relied on a ligand 3-D shape similarity virtual screening (VS) approach using the ROCS program as the VS tool and as query colchicine and TN-16, which both bind the α,β-tubulin dimer. One of the hits identified, using TN-16 as query, has been explored by the synthesis of its structural analogues, leading to 2-(1-((2-methoxyphenyl)amino)ethylidene)-5-phenylcyclohexane-1,3-dione (compound 16c) with an IC50 = 0.09 ± 0.01 μM in HMEC-1 and BAEC, being 100-fold more potent than the initial hit. Compound 16c caused cell cycle arrest in the G2/M phase and interacted with the colchicine-binding site in tubulin, as confirmed by a competition assay with N,N'-ethylenebis(iodoacetamide) and by fluorescence spectroscopy. Moreover, 16c destroyed an established endothelial tubular network at 1 μM and inhibited the migration and invasion of human breast carcinoma cells at 0.4 μM. In conclusion, our approach has led to a new chemotype of promising antiproliferative compounds with antimitotic and potential VDA properties.

High Throughput Screening of Natural Products for Anti‐mitotic Effects in MDA‐MB‐231 Human Breast Carcinoma Cells

Some of the most effective anti-mitotic microtubule-binding agents, such as paclitaxel (Taxus brevifolia) were originally discovered through robust National Cancer Institute botanical screenings. In this study, a high-through put microarray format was utilized to screen 897 aqueous extracts of commonly used natural products (0.00015-0.5 mg/mL) relative to paclitaxel for anti-mitotic effects (independent of toxicity) on proliferation of MDA-MB-231 cells. The data obtained showed that less than 1.34 % of the extracts tested showed inhibitory growth (IG50 ) properties <0.0183 mg/mL. The most potent anti-mitotics (independent of toxicity) were Mandrake root (Podophyllum peltatum), Truja twigs (Thuja occidentalis), Colorado desert mistletoe (Phoradendron flavescens), Tou Gu Cao [symbol: see text] Speranskia herb (Speranskia tuberculata), Bentonite clay, Bunge root (Pulsatilla chinensis), Brucea fruit (Brucea javanica), Madder root (Rubia tinctorum), Gallnut of Chinese Sumac (Melaphis chinensis), Elecampane root (Inula Helenium), Yuan Zhi [symbol: see text] root (Polygala tenuifolia), Pagoda Tree fruit (Melia Toosendan), Stone root (Collinsonia Canadensis), and others such as American Witchhazel, Arjun, and Bladderwrack. The strongest tumoricidal herbs identified from amongst the subset evaluated for anti-mitotic properties were wild yam (Dioscorea villosa), beth root (Trillium Pendulum), and alkanet root (Lithospermum canescens). Additional data was obtained on a lesser-recognized herb: (S. tuberculata), which showed growth inhibition on BT-474 (human ductal breast carcinoma) and Ishikawa (human endometrial adenocarcinoma) cells with ability to block replicative DNA synthesis, leading to G2 arrest in MDA-MB-231 cells. In conclusion, these findings present relative potency of anti-mitotic natural plants that are effective against human breast carcinoma MDA-MB-231 cell division.

Investigation of the potential use of a Gloriosa superba L. extract for the treatment of cancer

Gloriosa superba L. (Liliaceae) is traditionally used in Ayurveda for several purposes, such as the treatment of gout, snake bites, intestinal worms, etc. G. superba contains colchicine, which has antimitotic properties and it has been used in the treatment of cancer. However, because of the low therapeutic index, it is not used as an anticancer drug anymore. G. superba contains not only colchicine but also other, very similar alkaloids. In this project the G. superba extract is evaluated for its potential use in the treatment of cancer. The hypothesis is that a combination of various active compounds in an extract may have more beneficial effects than the pure compounds, due to synergism and the presence of prodrugs such as glycosides. The 80% ethanolic extract of the G. superba seeds was phytochemically investigated and colchicine, 3-O-demethylcolchicine and colchicoside were isolated and identified by means of HPLC-SPE-NMR. In order to prepare a quantified extract with a known amount of colchicine derivatives for future in vivo experiments, an analytical HPLC-method was developed and validated. The 80% ethanolic extract contained 1.3% of colchicoside, 1.3% of 3-O-demethylcolchicine and 2.9% of colchicine. The cytotoxicity of the 80% ethanolic extract was also determined on three different human cancer cell lines and a high cytotoxic effect was observed on the tested cell lines with an IC50 value of 0.340 ± 0.015 µg/mL (MDA-MB-231 WT), 0.167 µg/mL (PANC-1) and 0.167 ± 0.008 µg/mL (HT-29) using the sulforhodamine B assay.

Isolation and First Total Synthesis of PM050489 and PM060184, Two New Marine Anticancer Compounds

Microtubules continue to be one of the most successful anticancer drug targets and a favorite hit for many naturally occurring molecules. While two of the most successful representative agents in clinical use, the taxanes and the vinca alkaloids, come from terrestrial sources, the sea has also proven to be a rich source of new tubulin-binding molecules. We describe herein the first isolation, structural elucidation and total synthesis of two totally new polyketides isolated from the Madagascan sponge Lithoplocamia lithistoides . Both PM050489 and PM060184 show antimitotic properties in human tumor cells lines at subnanomolar concentrations and display a distinct inhibition mechanism on microtubules. The development of an efficient synthetic procedure has solved the supply problem and, following pharmaceutical development, has allowed PM060184 to start clinical studies as a promising new drug for cancer treatment.

Interaction of glia with a compliant, microstructured silicone surface

Soft bioengineered surfaces offer a route towards modulating the tissue responses to chronically implanted devices and may enhance their functionality. In this communication we fabricate microtopographically rich and mechanically compliant silicone surfaces for use in soft neural interfaces. We observe the interaction of primary rat microglia and astroglia with arrays of tall and short (4.7 and 0.5μm) vertically oriented polydimethylsiloxane (PDMS) micropillars and a flat PDMS surface in vitro. With the pillar size and spacing that we use (1.3μm diameter and 1.6μm edge to edge), glia are found to engulf and bend tall pillars. The cytoskeleton of cells adhering to the pillar arrays lacks actin stress fibers; instead we observe actin ring formations around individual pillars. Tall, but not short pillar arrays are inhibitory to migration and spreading for both microglia and astrocytes. When compared to a flat PDMS surface and short pillar arrays, tall micropillar arrays cause nearly a 2-fold decrease in proliferation rates for both cell types. The antimitotic properties of tall pillar arrays may be useful for reducing the density of the glial capsule around brain-implanted devices.