Mitotic drug targets and the development of novel anti-mitotic anticancer drugs

Schmidt, Mathias; Bastians, Holger

doi:10.1016/j.drup.2007.06.003

Cited by 175 publications

(165 citation statements)

References 163 publications

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“…Lignans represent one of the most important and interesting classes of biologically active compounds, because lignan molecules can induce cancer cell apoptosis (Ayella et al, 2010;Chavez et al, 2011;Huong et al, 2011;Singh et al, 2007;Xu et al, 2006Xu et al, , 2011. Podophyllotoxin inhibits microtubule assembly of the mitotic apparatus, acting as a competitive inhibitor of the binding site for colchicine to tubulin (Loike et al, 1978); this process occurs during mitosis, where the microtubules are rearranged to form the mitotic spindle, which is essential for cell division (Ayres & Loik, 1990;Islam & Iskander, 2004;Schmidt & Bastians, 2007).…”

Section: Discussionmentioning

confidence: 99%

Antiproliferative activity of yatein isolated fromAustrocedrus chilensisagainst murine myeloma cells: Cytological studies and chemical investigations

Donoso-Fierro

Tiezzi

Ovidi

et al. 2014

Pharmaceutical Biology

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Materials and methods:The antiproliferative activity of yatein, isotaxiresinol, ferruginol, and isorhamnetin was evaluated in vitro using the MTT assay. The effect of yatein at the cellular level, due to its high antiproliferative activity was evaluated. P3X cells treated for 24 h with 12.5 and 25 mg/mL of yatein were also examined at the cytological level using immunofluorescence and scanning and transmission electron microscopy.Results: Yatein, a lignan isolated from A. chilensis, potentially inhibited P3X murine myeloma cell proliferation, resulting in approximately 75% cell death in response to a 25 mg/mL treatment with the lignan. P3X cells lost membrane integrity at the nuclear and cytoplasmic levels, including organelles, in response to yatein treatment (12.5 mg/mL), and we observed changes in the cytoplasmic organization and distribution of microtubules. The other compounds tested had low activity. Discussion and conclusions: Yatein is a lignan precursor of podophyllotoxin, a key agent in anticancer drugs. Due to its structural similarities to podophyllotoxin, yatein could have similar cytoplasmic target(s), such as the microtubular apparatus. These findings suggest that yatein may be of potential pharmacological interest and warrants further investigation in human cell lines.

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Section: Discussionmentioning

confidence: 99%

Antiproliferative activity of yatein isolated fromAustrocedrus chilensisagainst murine myeloma cells: Cytological studies and chemical investigations

Donoso-Fierro

Tiezzi

Ovidi

et al. 2014

Pharmaceutical Biology

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“…Evidence from microtubule binding drugs suggests that proliferation of non-transformed cells, including hematopoetic precursor cells, might explain the severe myelosuppression and neutropenia observed in patients during therapy. 25 RNAi could overcome these adverse effects and show greater efficacy because of localized inhibition. 26 This concept has set up the path for therapeutic applications, both locally 27 and systemically.…”

Section: Introductionmentioning

confidence: 99%

Intratumor RNA interference of cell cycle genes slows down tumor progression

et al. 2011

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Small interfering RNAs (siRNAs) are emerging as promising therapeutic tools. However, the widespread clinical application of such molecules as modulators of gene expression is still dependent on several aspects that limit their bioavailability. One of the most promising strategies to overcome the barriers faced by gene silencing molecules involves the use of lipid-based nanoparticles (LNPs) and viral vectors, such as adenoviruses (Ads). The primary obstacle for translating gene silencing technology from an effective research tool into a feasible therapeutic strategy remains its efficient delivery to the targeted cell type in vivo. In this study, we tested the capability of LNPs and Ad to transduce and treat locally tumors in vivo. Efficient knockdown of a surrogate reporter (luciferase) and therapeutic target genes such as the kinesin spindle protein (KIF11) and polo-like kinase 1 were observed. Most importantly, this activity led to a cell cycle block as a consequence and slowed down tumor progression in tumor-bearing animals. Our data indicate that it is possible to achieve tumor transduction with si/short hairpin RNAs and further improve the delivery strategy that likely in the future will lead to the ideal non-viral particle for targeted cancer gene silencing.

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“…Due toEg5's essential function in mitosis, it is now an important target for the development of inhibitors that have antimitotic activity [7][8][9]. Following the discovery of monastrol [10], the first identified Eg5 inhibitor, a plethora of structurally related and unrelated inhibitors of Eg5 have been recently identified [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Mutations in the human kinesin Eg5 that confer resistance to monastrol and S-trityl-l-cysteine in tumor derived cell lines

Tcherniuk

Lis

Kozielski

et al. 2010

Biochemical Pharmacology

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. Mutations in the human kinesin Eg5 that confer resistance to monastrol and S-Trityl-L-Cysteine in tumor derived cell lines.. Biochemical Pharmacology, Elsevier, 2010, 79 (6) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. confirms the target specificity of monastrol and STLC for Eg5. These data also suggest a possible mechanism by which drug resistance may occur in tumors treated with agents targeting Eg5.

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Mitotic drug targets and the development of novel anti-mitotic anticancer drugs

Cited by 175 publications

References 163 publications

Antiproliferative activity of yatein isolated fromAustrocedrus chilensisagainst murine myeloma cells: Cytological studies and chemical investigations

Antiproliferative activity of yatein isolated fromAustrocedrus chilensisagainst murine myeloma cells: Cytological studies and chemical investigations

Intratumor RNA interference of cell cycle genes slows down tumor progression

Mutations in the human kinesin Eg5 that confer resistance to monastrol and S-trityl-l-cysteine in tumor derived cell lines

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