Drugs that target dynamic microtubules: A new molecular perspective

Stanton, Richard A.; Gernert, Kim M.; Nettles, James H.; Aneja, Ritu

doi:10.1002/med.20242

Cited by 466 publications

(372 citation statements)

References 213 publications

(278 reference statements)

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“…docetaxel) and vinca alkaloids (i.e., vinblastine, vincristine) are among the most effective in treating metastatic disease but their benefits are limited by the rapid development of resistance. 1,2 As such, there is still unmet need for selective therapeutic agents that not only target cell division and induce early cell death in the primary tumor but also suppress metastatic spread. 1 Chalcone is a key functional group appearing in numerous naturally occurring compounds with anticancer activities and in synthetic anti-tumor agents, 3,4 yet novel synthetic molecules with defined specificity are still needed.…”

Section: Introductionmentioning

confidence: 99%

Novel indolyl-chalcones target stathmin to induce cancer cell death

Węgiel

Jernigan

et al. 2016

Cell Cycle

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Efficacy of current therapies for advanced and metastatic cancers remains a challenge in clinical practice. We investigated the anti-cancer potency of 3 novel indoly-chalcones (CITs). Our results indicated the lead molecule CIT-026 (Formula D C 20 H 16 FNO) induced cell death in prostate and lung cancer cell lines at sub-micromolar concentration. CITs (CIT-026, CIT-214, CIT-223) lead to microtubule destabilization, cell death and low cell proliferation, which in part was dependent on stathmin (STMN1) expression. Knockdown of STMN1 with siRNA against STMN1 in part restored viability of cancer cells in response to CITs. Further, CIT-026 and CIT-223 blocked cancer cell invasion through matrigel-coated chambers. Mechanistically, CITs inhibited phosphorylation of STMN1 leading to STMN1 accumulation and mitotic catastrophe. In summary, we have synthetized novel anti-cancer CIT molecules and defined their mechanism of action in vitro.

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Section: Introductionmentioning

confidence: 99%

Novel indolyl-chalcones target stathmin to induce cancer cell death

Węgiel

Jernigan

et al. 2016

Cell Cycle

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“…3 Disturbed microtubule kinetics prevent satisfaction of the spindle assembly checkpoint (SAC) and hence arrest cells at metaphase. The SAC is a mitotic surveillance mechanism that senses improper attachment of chromosomes to the mitotic spindle.…”

Section: Introductionmentioning

confidence: 99%

BubR1 is frequently repressed in acute myeloid leukemia and its re-expression sensitizes cells to antimitotic therapy

Schnerch¹,

Schmidts²,

Follo³

et al. 2013

Haematologica

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ABSTRACT© F e r r a t a S t o r t i F o u n d a t i o n 2 0 1 3 blasts investigated. By performing functional studies both in non-responsive myeloblastic and responsive lymphoblastic cells, we investigated how reconstitution of the SAC and interference with SAC activity translate into response to spindle poison. Using live-cell imaging, retrovirus-delivered inducible knockdown and overexpression, we demonstrate that re-expression of BubR1 in myeloblastic cells confers an improved response to spindle poison. Methods Cell culturesCell lines were cultured as described in the DSMZ (Human and Animal Cell Lines Database, Braunschweig, Germany) datasheets. Synchronization procedures, interference with microtubule kinetics, proteasome inhibition and antibiotic selection were performed as outlined in the Online Supplementary Appendix.Primary blasts from AML patients were isolated and cultured as described in the Online Supplementary Appendix. The analyses were carried out after approval by the local Ethics Committee according to the guidelines of the Declaration of Helsinki and good clinical practice. Informed consent was obtained from the patients. Live-cell imaging kineticsCells were seeded in eight-well microscope chambers (Ibidi) that were coated with fibrinogen or collagen IV, at a concentration of 30,000 and 60,000 cells per well and imaged as previously described. 13 Retroviral transductionRetroviral particles were produced using Phoenix alpha packaging cells and inducible cell lines were established according to the manufacturer's instructions. Detailed information concerning oligonucleotide sequences and the backbones used is provided in the Online Supplementary Appendix. In vitro ubiquitinationThe APC/C was immunopurified from DG-75 and Kasumi-1 cells using an anti-Cdc27 antibody (Sigma-Aldrich) and Protein Gagarose. Ubiquitination reactions using precipitated APC/C were performed in the presence of in vitro transcribed/translated 35S-marked cyclin B as described in detail in the Online Supplementary Appendix. Western blot analysisWestern blotting was performed as described previously 13 using the antibodies specified in the Online Supplementary Appendix. Flow cytometryCell cycle distribution and BubR1 expression in single cells were determined using a FACSCalibur (Becton Dickinson). Microarray data and data processingMicroarray datasets were obtained from the open-access NIH Gene-Expression Omnibus (GEO) database. Datasets used in our analysis were GSE30029 18 and GSE13204.19 Data analysis and statistical analysisTIFF image stacks were analyzed using LSM Image Browser (v.2.80.1123) (Carl Zeiss). Calculations and statistics were done in Microsoft Excel 2002 and/or GraphPad Prism V5.03 (GraphPad Software Inc.). P values <0.05 were considered statistically significant. The statistical test used was an unpaired t-test (two-tailed) with a confidence interval of 95%. Results The mitotic checkpoint protein BubR1 is repressed in acute myeloid leukemiaTo address the expression levels of the regulatory proteins BubR1, ...

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“…This phenotype was recapitulated by nocodazole, a known tubulin depolymerizer. This result was not altogether unexpected, given that several clinically used antimitotics target tubulin polymerization dynamics 41 . Using an in vitro tubulin polymerization assay it was established that (S)-41 acts as a tubulin-depolymerizing agent 42 , similar to our positive control nocodazole (Fig.…”

Section: Library Synthesismentioning

confidence: 77%

Diversity-oriented synthesis as a tool for identifying new modulators of mitosis

et al. 2014

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The synthesis of diverse three-dimensional libraries has become of paramount importance for obtaining better leads for drug discovery. Such libraries are predicted to fare better than traditional compound collections in phenotypic screens and against difficult targets. Herein we report the diversity-oriented synthesis of a compound library using rhodium carbenoid chemistry to access structurally diverse three-dimensional molecules and show that they access biologically relevant areas of chemical space using cheminformatic analysis. Highcontent screening of this library for antimitotic activity followed by chemical modification identified 'Dosabulin', which causes mitotic arrest and cancer cell death by apoptosis. Its mechanism of action is determined to be microtubule depolymerization, and the compound is shown to not significantly affect vinblastine binding to tubulin; however, experiments suggest binding to a site vicinal or allosteric to Colchicine. This work validates the combination of diversity-oriented synthesis and phenotypic screening as a strategy for the discovery of biologically relevant chemical entities.

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Drugs that target dynamic microtubules: A new molecular perspective

Cited by 466 publications

References 213 publications

Novel indolyl-chalcones target stathmin to induce cancer cell death

Novel indolyl-chalcones target stathmin to induce cancer cell death

BubR1 is frequently repressed in acute myeloid leukemia and its re-expression sensitizes cells to antimitotic therapy

Diversity-oriented synthesis as a tool for identifying new modulators of mitosis

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