Low Concentrations of Taxol Cause Mitotic Delay Followed by Premature Dissociation of p55CDC from Mad2 and BubR1 and Abrogation of the Spindle checkpoint, Leading to Aneuploidy

Ikui, Amy E.; Yang, Chia-Ping Huang; Matsumoto, Tomohiro; Horwitz, Susan Band

doi:10.4161/cc.4.10.2061

Cited by 64 publications

(75 citation statements)

References 14 publications

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“…To determine if the lack of mitotic arrest in arsenite-resistant cell lines was due to decreased spindle checkpoint function, all four melanoma cell lines were treated with the spindle checkpoint-activating agent paclitaxel (Ikui et al, 2005) ranging from 0 to 300 nM and mitotic indices were determined after 24 h of treatment. Paclitaxel caused a robust increase in the mitotic index of arsenite-sensitive A375 and SK-Mel-2 cells with a concentration of 100 nM paclitaxel increasing the mitotic index to 61 and 40%, respectively ( Figure 7A).…”

Section: Resultsmentioning

confidence: 99%

Sensitivity to sodium arsenite in human melanoma cells depends upon susceptibility to arsenite-induced mitotic arrest

McNeely

Belshoff

Taylor

et al. 2008

Toxicology and Applied Pharmacology

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Arsenic induces clinical remission in patients with acute promyelocytic leukemia and has potential for treatment of other cancers. The current study examines factors influencing sensitivity to arsenic using human malignant melanoma cell lines. A375 and SK-Mel-2 cells were sensitive to clinically achievable concentrations of arsenite, whereas SK-Mel-3 and SK-Mel-28 cells required supratherapeutic levels for toxicity. Inhibition of glutathione synthesis, glutathione S-transferase (GST) activity, and multidrug resistance protein (MRP) transporter function attenuated arsenite resistance, consistent with studies suggesting arsenite is extruded from the cell as a glutathione conjugate by MRP-1. However, MRP-1 was not overexpressed in resistant lines and GST-π was only slightly elevated. ICP-MS analysis indicated arsenite-resistant SK-Mel-28 cells did not accumulate less arsenic than arsenite-sensitive A375 cells, suggesting resistance was not attributable to reduced arsenic accumulation but rather to intrinsic properties of resistant cell lines. The mode of arseniteinduced cell death was apoptosis. Arsenite-induced apoptosis is associated with cell cycle alterations. Cell cycle analysis revealed arsenite-sensitive cells arrested in mitosis whereas arsenite-resistant cells did not, suggesting induction of mitotic arrest occurs at lower intracellular arsenic concentrations. Higher intracellular arsenic levels induced cell cycle arrest in S-phase and G 2 -phase in SK-Mel-3 and SK-Mel-28 cells, respectively. The lack of arsenite-induced mitotic arrest in resistant cell lines was associated with a weakened spindle checkpoint resulting from reduced expression of spindle checkpoint protein BUBR1. These data suggest arsenite has potential for treatment of solid tumors but a functional spindle checkpoint is a prerequisite for a positive response to its clinical application.

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Section: Resultsmentioning

confidence: 99%

Sensitivity to sodium arsenite in human melanoma cells depends upon susceptibility to arsenite-induced mitotic arrest

McNeely

Belshoff

Taylor

et al. 2008

Toxicology and Applied Pharmacology

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“…The chemotherapeutic drug Taxol triggers cell death by inactivating the spindle checkpoint, thus inducing aneuploidy and aberrant mitosis (39). Kinase inhibitors that have the same effects on tumor cells might therefore be helpful adjuncts when used in combination with chemotherapeutic drugs based on other strategies.…”

Section: Discussionmentioning

confidence: 99%

Role of Nek2 on centrosome duplication and aneuploidy in breast cancer cells

et al. 2013

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Breast cancer is the most common solid tumor and the second most common cause of death in women. Despite a large body of literature and progress in breast cancer research, many molecular aspects of this complex disease are still poorly understood, hindering the design of specific and effective therapeutic strategies. To identify molecules important in breast cancer progression and metastasis, we tested the in vivo effects of inhibiting the functions of various kinases and genes involved in the regulation/modulation of the cytoskeleton by downregulating them in mouse PyMT mammary tumor cells and human breast cancer cell lines. These kinases and cytoskeletal regulators were selected based on their prognostic values for breast cancer patient survival. PyMT tumor cells in which a selected gene was stably knocked down were injected into the tail veins of mice and the formation of tumors in the lungs was monitored. One of several genes found to be important for tumor growth in lungs was Nek2, a cell cycle-related protein kinase. Furthermore, Nek2 was also important for tumor growth in the mammary fat pad.In various human breast cancer cell lines, Nek2 knockdown induced aneuploidy and cell cycle arrest that led to cell death. Significantly, the breast cancer cell line most sensitive to Nek2 depletion was of the triple negative breast cancer subtype. Our data indicate that Nek2 plays a pivotal role in breast cancer growth at primary and secondary sites, and thus may be an attractive and novel therapeutic target for this disease.

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“…It has been reported that paclitaxel's induction of apoptosis can occur due to aberrant mitosis or to entering a multinucleated G1-like state subsequent to mitotic slippage, depending on cell type and drug schedule (Abal et al, 2003). A recent study reported that high paclitaxel treatment causes well sustained spindle checkpoint activation leading to mitotic block, while low concentrations below 10 nM cause mitotic delay but premature abrogation of the spindle checkpoint leading to aneuploidy (Ikui et al, 2005). We observed a similar phenomenon comparing low and high paclitaxel levels (supplementary data).…”

Section: Discussionmentioning

confidence: 99%

Arsenite-induced mitotic death involves stress response and is independent of tubulin polymerization

Taylor

McNeely

Miller

et al. 2008

Toxicology and Applied Pharmacology

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Arsenite, a known mitotic disruptor, causes cell cycle arrest and cell death at anaphase. The mechanism causing mitotic arrest is highly disputed. We compared arsenite to the spindle poisons nocodazole and paclitaxel. Immunofluorescence analysis of α-tubulin in interphase cells demonstrated that, while nocodazole and paclitaxel disrupt microtubule polymerization through destabilization and hyperpolymerization, respectively, microtubules in arsenite-treated cells remain comparable to untreated cells even at supra-therapeutic concentrations. Immunofluorescence analysis of α-tubulin in mitotic cells showed spindle formation in arsenite-and paclitaxel-treated cells but not in nocodazole-treated cells. Spindle formation in arsenite-treated cells appeared irregular and multi-polar. γ-tubulin staining showed that cells treated with nocodazole and therapeutic concentrations of paclitaxel contained two centrosomes. In contrast, most arsenite-treated mitotic cells contained more than two centrosomes, similar to centrosome abnormalities induced by heat shock. Of the three drugs tested, only arsenite treatment increased expression of the inducible isoform of heat shock protein 70 (HSP70i). HSP70 and HSP90 proteins are intimately involved in centrosome regulation and mitotic spindle formation. HSP90 inhibitor 17-DMAG sensitized cells to arsenite treatment and increased arsenite-induced centrosome abnormalities. Combined treatment of 17-DMAG and arsenite resulted in a supra-additive effect on viability, mitotic arrest, and centrosome abnormalities. Thus, arsenite-induced abnormal centrosome amplification and subsequent mitotic arrest is independent of effects on tubulin polymerization and may be due to specific stresses that are protected against by HSP90 and HSP70.

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Low Concentrations of Taxol Cause Mitotic Delay Followed by Premature Dissociation of p55CDC from Mad2 and BubR1 and Abrogation of the Spindle checkpoint, Leading to Aneuploidy

Cited by 64 publications

References 14 publications

Sensitivity to sodium arsenite in human melanoma cells depends upon susceptibility to arsenite-induced mitotic arrest

Sensitivity to sodium arsenite in human melanoma cells depends upon susceptibility to arsenite-induced mitotic arrest

Role of Nek2 on centrosome duplication and aneuploidy in breast cancer cells

Arsenite-induced mitotic death involves stress response and is independent of tubulin polymerization

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