Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Thalicthuberine: A Novel Mitotic Inhibitor in Prostate Cancer Cells

ABSTRACT: Bioassay-guided fractionation of a cytotoxic extract derived from the Australian endemic plant Hernandia albiflora (twigs) resulted in the isolation of the two known compounds: deoxypodophyllotoxin and thalicthuberine. Both compounds were tested for their inhibition of LNCaP cell viability. Thalicthuberine (TH, IC50=2.0 µM) was selected for mechanism of action studies. Ongoing investigations have shown that TH induced a strong accumulation of LNCaP cells in mitosis, severe mitotic spindle defects and asymmetric cell divisions, ultimately leading to mitotic catastrophe accompanied by cell death through apoptosis. However, unlike microtubule-targeting drugs (vinblastine, paclitaxel and nocodazole), TH did not affect tubulin polymerization in a cell-free system, while it reduced cellular microtubule polymer mass, suggesting that TH indirectly targets microtubule dynamics through inhibition of critical regulators or tubulin-associated proteins. Based on phenotypic comparisons, we excluded the mitotic regulators Aurora kinase A and Polo-like kinase 1 as potential targets of TH. TH did not directly interact with DNA (cell-free assay) or induce DNA damage in cells. Further experiments will attempt to address the molecular target(s) and inhibition mechanism of TH. This is the first report of a mechanism of action study for this natural product. Based on these results, TH has great promise for further development into a potent non-tubulin-targeting mitotic inhibitor.

ORGANISM(S): Homo sapiens

PROVIDER: GSE83459 | GEO | 2016/06/17

SECONDARY ACCESSION(S): PRJNA326022

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

6-acetoxy-anopterine: A novel structure class of mitotic inhibitor disrupting microtubule dynamics in prostate cancer cells

Project description:The lack of a cure for metastatic prostate cancer (PCa) highlights the urgent need for more efficient drugs to fight this disease. Here, we report the molecular mechanism of action of the natural product 6-acetoxy-anopterine (6-AA) in malignant cells of the prostate. This potent cytotoxic alkaloid from the endemic Australian tree Anopterus macleayanus induced at low nanomolar doses a strong accumulation of LNCaP and PC3 PCa cells in mitosis, severe mitotic spindle defects and asymmetric cell divisions, ultimately leading to mitotic catastrophe accompanied by cell death through apoptosis. DNA microarray of 6-AA treated LNCaP cells combined with pathway analysis identified very similar transcriptional changes when compared to vinblastine, highlighting pathways involved in mitosis, microtubule spindle organisation and microtubule binding. Like vinblastine, 6-AA inhibited microtubule polymerization in a cell-free system and reduced microtubule polymer mass in vitro. Yet, microtubule alterations that are associated with resistance to microtubule-destabilizing drugs like vinca alkaloids or 2-methoxyestradiol did not confer cross-resistance to 6-AA, suggesting a different mechanism of microtubule interaction. Finally, 6-AA is the first-in-class microtubule inhibitor that features the unique anopterine scaffold. Altogether, this study provides a strong rationale to further develop this novel structure class of microtubule inhibitor for the treatment of malignant disease.

2016-05-11 | GSE81277 | GEO

Cardiotoxicity of tubulin binders

Project description:The use of tubulin binders (TBs) in oncology indications often is associated with cardiotoxicity, the mechanism of which has not been elucidated. We observed that a single administration of TBs to rats caused an increase in the number of mitotic figures in the myocardial interstitium after 24 hours. We therefore hypothesized that interstitial cells are the primary target of TBs. To test this hypothesis, we evaluated the acute effects of a single intravenous administration of 3 reference TBs, colchicine (0.2 and 2 mg/kg), vinblastine (0.5 and 3 mg/kg), and vincristine (0.1 and 1 mg/kg) 6 and 24 hours after dosing. Mitotic arrest was identified at 24 hours in all high-dose groups based on an increase in the number of mitotic figures in the interstitium coupled with a dramatic decrease in the number of Ki67-positive interstitial cells. Analysis of the myocardial transcriptomic data further supported G2/M cell cycle arrest 6 hours after dosing with the high-dose groups of all 3 compounds. Apoptotic figures and an increase in the number of cleaved caspase 3-positive cells were identified at 6 and 24 hours at the highest dose of each compound almost exclusively in interstitial cells; a few cardiomyocytes were affected as well. Transcriptomic data further suggested that some of the affected interstitial cells were endothelial cells based on the up-regulation of genes typically associated with vascular damage and down-regulation of Endothelial Cell-Specific Molecule 1 and Apelin. Taken together, these data identify endothelial cells of the myocardium as the primary target of the cardiotoxicity of TBs and identify cell cycle arrest as the mechanism of this toxicity. Gene expression was profiled in the myocardium of rats at 6 and 24 hr after a single dose of colchicine, vinblastine or vincristine.

2010-01-01 | E-GEOD-19290 | biostudies-arrayexpress

Breast cancer cell lines treated with eribulin and paclitaxel

Project description:Eribulin mesylate is a synthetic macrocyclic ketone analog of the marine sponge natural product halichondrin B. Eribulin is a mechanistically unique inhibitor of microtubule dynamics, leading to inhibition of microtubule growth in the absence of effects on microtubule shortening at microtubule plus ends, and formation of nonproductive tubulin aggregates. In this study, we investigated whether selective signal pathways were associated with eribulin activity compared to paclitaxel, which stabilizes microtubules, based on gene expression profiling of cell line panels of breast, endometrial, and ovarian cancer in vitro. 27 breast cancer cell lines treated with eribulin and paclitaxel for 24 hours at concentration 10xIC50. Three technical replicates were included. for eribulin , paclitaxel and untreated cell lines.

2014-10-02 | E-GEOD-50811 | biostudies-arrayexpress

Endometrial cancer cell lines treated with eribulin and paclitaxel

Project description:Eribulin mesylate is a synthetic macrocyclic ketone analog of the marine sponge natural product halichondrin B. Eribulin is a mechanistically unique inhibitor of microtubule dynamics, leading to inhibition of microtubule growth in the absence of effects on microtubule shortening at microtubule plus ends, and formation of nonproductive tubulin aggregates. In this study, we investigated whether selective signal pathways were associated with eribulin activity compared to paclitaxel, which stabilizes microtubules, based on gene expression profiling of cell line panels of breast, endometrial, and ovarian cancer in vitro. 19 endometrial cancer cell lines treated with eribulin and paclitaxel for 24 hours at concentration 10xIC50. Three technical replicates were included. for eribulin , paclitaxel and untreated cell lines.

2014-10-02 | E-GEOD-50830 | biostudies-arrayexpress

Ovarian cancer cell lines treated with eribulin and paclitaxel

Project description:Eribulin mesylate is a synthetic macrocyclic ketone analog of the marine sponge natural product halichondrin B. Eribulin is a mechanistically unique inhibitor of microtubule dynamics, leading to inhibition of microtubule growth in the absence of effects on microtubule shortening at microtubule plus ends, and formation of nonproductive tubulin aggregates. In this study, we investigated whether selective signal pathways were associated with eribulin activity compared to paclitaxel, which stabilizes microtubules, based on gene expression profiling of cell line panels of breast, endometrial, and ovarian cancer in vitro. 21 ovarian cancer cell lines treated with eribulin and paclitaxel for 24 hours at concentration 10xIC50. Three technical replicates were included for eribulin , paclitaxel and untreated cell lines.

2014-10-02 | E-GEOD-50831 | biostudies-arrayexpress

Transcription profiling of human A549 lung cancer cells treated with compounds from a series of inhibitors developed against the human LIM kinases LIMK1 and LIMK2

Project description:To investigate an unknown mechanism of cytotoxicity, A549 human lung-cancer cells were treated with compounds from a series of inhibitors developed against the human LIM kinases LIMK1 and LIMK2. Compounds 1 and 2 inhibit LIM kinase activity in vitro and affect cell proliferation and survival in vivo. Compounds 3 and 4 inhibit LIM kinases but do not affect cell survival or proliferation. Compounds 5 and 6 affect proliferation and survival but do not inhibit LIM kinases. Nocodazole was included as a comparator because the compounds were known to affect microtubule stability. A treatment of 7 hours was used to examine events prior to apoptosis, while the dose levels captured both cytotoxicity and inhibition of LIMKs (Compounds 1 and 2), LIMK inhibition alone ( Compounds 3 and 4) or cytotoxicity alone (Compounds 5, 6, and Nocodazole).

2008-09-17 | E-TABM-450 | biostudies-arrayexpress

A novel tubulin binding molecule drives differentiation of acute myeloid leukaemia cells

Project description:Here we perform a phenotypic screen and identified novel compounds that can promote differentiation in several AML cell lines. Lead compounds are able to decrease tumour burden and increase survival in vivo. Using multiple complementary target deconvolution approaches (including chemoproteomics), these compounds were revealed to be anti-mitotic tubulin disruptors that cause differentiation by inducing a G2-M mitotic arrest. Together, these results reveal a novel function for tubulin disruptors in causing differentiation of AML cells.

2021-11-02 | PXD022038 | Pride

Endometrial cancer cell lines treated with eribulin and paclitaxel

2014-10-02 | GSE50830 | GEO

Ovarian cancer cell lines treated with eribulin and paclitaxel

2014-10-02 | GSE50831 | GEO

Breast cancer cell lines treated with eribulin and paclitaxel

2014-10-02 | GSE50811 | GEO