Disruption of microtubule assembly and spindle formation as a mechanism for the induction of aneuploid cells by sodium arsenite and vanadium pentoxide

Ramírez, Patricia; Eastmond, David A.; Laclette, Juan Pedro; Ostrosky‐Wegman, Patricia

doi:10.1016/s1383-5742(97)00018-5

Cited by 165 publications

(77 citation statements)

References 23 publications

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“…High concentration paclitaxel resulted in many apparently mono-polar spindles (Figure 2). A commonly suggested mechanism of arsenite-induced mitotic arrest is based on arsenite inhibiting tubulin polymerization through sulfhydryl binding in the GTP binding site of β-tubulin (Ramirez et al, 1997;Li and Broome, 1999;Carre et al, 2002;Kligerman et al, 2005). On the contrary, we observed clear formation of a mitotic spindle apparatus in all arsenite-treated mitotic cells, in contrast to nocodazole-treated cells (Figure 2).…”

Section: Discussionmentioning

confidence: 60%

“…The mechanism through which arsenite causes mitotic arrest is highly disputed. Most explanations focus on tubulin as the direct target of arsenite, however much conflict exists in the literature debating whether the mechanism involves tubulin stabilization (Huang and Lee, 1998;Ling et al, 2002), inhibition of tubulin polymerization (Ramirez et al, 1997;Li and Broome, 1999;Carre et al, 2002;Kligerman et al, 2005), or even if there is any effect on tubulin polymerization/organization at all (Li and Chou, 1992;Halicka et al, 2002). Thus, the mechanism for arsenite-induced mitotic arrest is still unresolved.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 60%

Section: Introductionmentioning

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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“…However, it was interesting to note that V (V) unlike Cr (VI) caused a temporary increase in G1 in the hTERTÀ cells without tetraploidy which was not seen in the hTERT þ cells that did undergo tetraploidy (83% G1 hTERTÀ, 63% G1 hTERT þ ). Vanadium unlike chromium is known to inhibit microtubule assembly and induce tubulin depolymerization (Ramirez et al, 1997). Lanni and Jacks (1998) showed that adaption to another microtubule destabilizing drug (nocodazole) caused a p53-dependent G1 arrest.…”

Section: Metal-induced Genomic Instabilitymentioning

confidence: 99%

“…V(V) is not known to cause double-strand breaks but induces DNA single-strand breaks and DNA-protein cross links (Ivancsits et al, 2002) and also increases the frequency of sister chromatid exchanges. It also interferes with microtubule assembly and spindle formation to induce aneuploidy (Ramirez et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Effects of hTERT on metal ion-induced genomic instability

et al. 2006

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There is currently a great interest in delayed chromosomal and other damaging effects of low-dose exposure to a variety of pollutants which appear collectively to act through induction of stress-response pathways related to oxidative stress and ageing. These have been studied mostly in the radiation field but evidence is accumulating that the mechanisms can also be triggered by chemicals, especially heavy metals. Humans are exposed to metals, including chromium (Cr) (VI) and vanadium (V) (V), from the environment, industry and surgical implants. Thus, the impact of low-dose stress responses may be larger than expected from individual toxicity projections. In this study, a short (24 h) exposure of human fibroblasts to low doses of Cr (VI) and V (V) caused both acute chromosome damage and genomic instability in the progeny of exposed cells for at least 30 days after exposure. Acutely, Cr (VI) caused chromatid breaks without aneuploidy while V (V) caused aneuploidy without chromatid breaks. The longerterm genomic instability was similar but depended on hTERT positivity. In telomerase-negative hTERTÀ cells, Cr (VI) and V (V) caused a long lasting and transmissible induction of dicentric chromosomes, nucleoplasmic bridges, micronuclei and aneuploidy. There was also a long term and transmissible reduction of clonogenic survival, with an increased b-galactosidase staining and apoptosis. This instability was not present in telomerasepositive hTERT þ cells. In contrast, in hTERT þ cells the metals caused a persistent induction of tetraploidy, which was not noted in hTERTÀ cells. The growth and survival of both metal-exposed hTERT þ and hTERTÀ cells differed if they were cultured at subconfluent levels or plated out as colonies. Genomic instability is considered to be a driving force towards cancer. This study suggests that the type of genomic instability in human cells may depend critically on whether they are telomerase-positive or -negative and that their sensitivities to metals could depend on whether they are clustered or diffuse.

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“…Alternatively, the National Research Council's report on arsenic in drinking water posited the induction of aneuploidy was the most likely mechanism of arsenic carcinogenesis (National Research Council, 1999). The aneuploidogenic nature of arsenic may be related to its capacity to perturb mitotic progression (Ramirez et al, 1997).…”

Section: Introductionmentioning

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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Disruption of microtubule assembly and spindle formation as a mechanism for the induction of aneuploid cells by sodium arsenite and vanadium pentoxide

Cited by 165 publications

References 23 publications

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

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

Effects of hTERT on metal ion-induced genomic instability

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

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