Interference of a novel indolylmaleimide with microtubules induces mitotic arrest and apoptosis in human progenitor and cancer cells

Eisenlöffel, Christian; Schmöle, Anne-Caroline; Pews‐Davtyan, Anahit; Brennführer, Anne; Kuznetsov, Sergei A.; Hübner, Rayk; Frech, Stefanie; Schult, Catrin; Junghanß, Christian; Beller, Matthias; Rolfs, Arndt; Frech, Moritz J.

doi:10.1016/j.bcp.2012.12.013

Cited by 11 publications

(20 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous studies on human ALL cell lines have shown a significant inhibition of proliferation starting at a concentration of 0.5 μM PDA-66 [11]. In the ReNcell VM human neural progenitor cell line (hNPC), proliferation can be stopped by application of 3 μM PDA-66 while human neuroblastoma cells (SH-SY5Y) with an IC 50 of 8.48 μM and lung cancer cells (A549) with an IC 50 of 4.97 μM were less sensitive to PDA-66 [12]. …”

Section: Discussionmentioning

confidence: 99%

“…PDA-66 and PDA-377 are two arylindolylmaleimides representing analogues of the GSK-3-specific inhibitor SB-216763 characterized by differences in their chemical substitutions [11, 12]. Application of PDA-66 to human acute lymphoblastic leukemia (ALL) cell lines induced significant anti-proliferative effects leading to apoptosis but did not inhibit GSK-3 significantly at protein level [11].…”

Section: Introductionmentioning

confidence: 99%

“…Application of PDA-66 to human acute lymphoblastic leukemia (ALL) cell lines induced significant anti-proliferative effects leading to apoptosis but did not inhibit GSK-3 significantly at protein level [11]. Previously, PDA-66 was reported to have a depolymerizing effect on tubulin assembly in vitro inducing microtubule destabilization in differentiated human neural progenitor cells [12]. However, the effects of PDA-66 and PDA-377 on lymphoma cells have not been characterized before.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Characterization of the novel indolylmaleimides' PDA-66 and PDA-377 effect on canine lymphoma cells

Beck²,

Schmidt

et al. 2016

Oncotarget

Self Cite

View full text Add to dashboard Cite

Protein kinase inhibitors are widely used in chemotherapeutic cancer regimens. Maleimide derivatives such as SB-216763 act as GSK-3 inhibitor targeting cell proliferation, cell death and cell cycle progression.Herein, the two arylindolylmaleimide derivatives PDA-66 and PDA-377 were evaluated as potential chemotherapeutic agents on canine B-cell lymphoma cell lines. Canine lymphoma represents a naturally occurring model closely resembling the human high-grade non-Hodgkin's lymphoma (NHL). PDA-66 showed more pronounced effects on both cell lines. Application of 2.5μM PDA-66 resulted in a significant induction of apoptosis (approx. 11 %), decrease of the metabolic activity (approx. 95 %), anti-proliferative effect (approx. 85 %) and cell death within 48h. Agent induced mode of action was characterized by whole transcriptome sequencing, 12 h and 24 h post-agent exposure. Key PDA-66-modulated pathways identified were cell cycle, DNA replication and p53 signaling. Expression analyses indicated that the drug acting mechanism is mediated through DNA replication and cycle arrest involving the spindle assembly checkpoint.In conclusion, both PDA derivatives displayed strong anti-proliferation activity in canine B-cell lymphoma cells. The cell and molecular PDA-induced effect characterization and the molecular characterization of the agent acting mechanism provides the basis for further evaluation of a potential drug for canine lymphoma serving as model for human NHL.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Characterization of the novel indolylmaleimides' PDA-66 and PDA-377 effect on canine lymphoma cells

Beck²,

Schmidt

et al. 2016

Oncotarget

Self Cite

View full text Add to dashboard Cite

show abstract

“…Disturbance of microtubule dynamics is one of the major mechanisms in stimulating mitotic arrest of cell cycle (Eisenlöffel et al 2013;Chan and Yen 2003). Microtubule assembly experiments were performed which separated assembly and disassembly microtubules in particulate and soluble fractions, respectively.…”

Section: Zerumbone Induces Disassembly Of Microtubule and Mitotic Arrmentioning

confidence: 98%

Zerumbone, a ginger sesquiterpene, induces apoptosis and autophagy in human hormone-refractory prostate cancers through tubulin binding and crosstalk between endoplasmic reticulum stress and mitochondrial insult

Chan

Liang

Hsu

et al. 2015

Naunyn-Schmiedeberg's Arch Pharmacol

View full text Add to dashboard Cite

Zerumbone, a natural monocyclic sesquiterpene, is the main component of the tropical plant Zingiber zerumbet Smith. Zerumbone induced antiproliferative and apoptotic effects against PC-3 and DU-145, two human hormone-refractory prostate cancer (HRPC) cell lines. Zerumbone inhibited microtubule assembly and induced an increase of MPM-2 expression (specific recognition of mitotic proteins). It also caused an increase of phosphorylation of Bcl-2 and Bcl-xL, two key events in tubulin-binding effect, indicating tubulin-binding capability and mitotic arrest to zerumbone action. Furthermore, zerumbone induced several cellular effects distinct from tubulin-binding properties. First, zerumbone significantly increased, while paclitaxel (as a tubulin-binding control) decreased, Mcl-1 protein expression. Second, paclitaxel but not zerumbone induced Cdk1 activity. Third, zerumbone other than paclitaxel induced Cdc25C downregulation. The data suggest that, in addition to targeting tubulin/microtubule, zerumbone may act on other targets for signaling transduction. Zerumbone induced mitochondrial damage and endoplasmic reticulum (ER) stress as evidenced by the loss of mitochondrial membrane potential and upregulation of GRP-78 and CHOP/GADD153 expression. Zerumbone induced an increase of intracellular Ca(2+) levels, a crosstalk marker between ER stress and mitochondrial insult, associated with the formation of active calpain I fragment. It induced apoptosis through a caspase-dependent way and caused autophagy as evidenced by dramatic LC3-II formation. In summary, the data suggest that zerumbone is a multiple targeting compound that inhibits tubulin assembly and induces a crosstalk between ER stress and mitochondrial insult, leading to apoptosis and autophagy in HRPCs.

show abstract

“…Both M arrest and apoptosis contribute to their anticancer effects (3,4,6). Besides, other mechanisms of action and/ or signaling pathways might be involved.…”

Section: Introductionmentioning

confidence: 99%

MCL-1 Degradation Mediated by JNK Activation via MEKK1/TAK1-MKK4 Contributes to Anticancer Activity of New Tubulin Inhibitor MT189

Wang

Meng

et al. 2014

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Colchicine site-targeted tubulin inhibitors are a promising type of anticancer drugs. MT189 is a new derivative of MT119, a previously reported colchicine site-binding antitubulin agent. In this study, MT189 was demonstrated to retain the property of MT119 in disrupting microtubulin via binding to the colchicine site, causing mitotic arrest and inducing apoptosis, and to display 8.7-fold enhanced proliferative inhibition in a panel of cancer cells. MT189 was shown to elicit in vivo anticancer effects on MDA-MB-231 xenografts in nude mice, and the tumor growth was suppressed by 35.9% over 14 days. MT189 led to degradation of MCL-1, a member of the antiapoptotic BCL-2 protein family. Its overexpression reduced but its silenced expression increased the apoptotic induction followed by the treatment with MT189. Moreover, the treatment with MT189 caused activation of the MEKK1/TAK1-MKK4-JNK signaling pathway. The activated JNK resulted in phosphorylation of MCL-1, which facilitated its ubiquitination-mediated degradation. Our results show that MT189 inhibits microtubulin polymerization by binding to the colchicine site. Relief of apoptotic suppression by MCL-1 degradation together with mitotic arrest contributes to the anticancer activity of MT189. Mol Cancer Ther; 13(6); 1480-91. Ó2014 AACR.

show abstract

Interference of a novel indolylmaleimide with microtubules induces mitotic arrest and apoptosis in human progenitor and cancer cells

Cited by 11 publications

References 34 publications

Characterization of the novel indolylmaleimides' PDA-66 and PDA-377 effect on canine lymphoma cells

Characterization of the novel indolylmaleimides' PDA-66 and PDA-377 effect on canine lymphoma cells

Zerumbone, a ginger sesquiterpene, induces apoptosis and autophagy in human hormone-refractory prostate cancers through tubulin binding and crosstalk between endoplasmic reticulum stress and mitochondrial insult

MCL-1 Degradation Mediated by JNK Activation via MEKK1/TAK1-MKK4 Contributes to Anticancer Activity of New Tubulin Inhibitor MT189

Contact Info

Product

Resources

About