Arsenite Disrupts Mitosis and Induces Apoptosis in SV40-Transformed Human Skin Fibroblasts

States, J. Christopher; Reiners, John J.; Pounds, Joel G.; Kaplan, David J.; Beauerle, Brian D.; McNeely, Samuel C.; Mathieu, Patricia; McCabe, Michael J.

doi:10.1006/taap.2002.9376

Cited by 50 publications

(43 citation statements)

References 26 publications

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“…To narrow the field of possible molecular targets of arsenite, it is desirable to define the cell cycle phase during which cells are most sensitive. Here, we present evidence that supports previous findings that G 2 /M cells are most sensitive to arsenite-induced cell cycle arrest leading to apoptosis (Li and Broome, 1999;Park et al, 2001;Halicka et al, 2002;Ling et al, 2002;States et al, 2002;Cai et al, 2003). However, another dramatic effect of arsenite is an induction of nonphase-specific cell cycle prolongation (i.e., arsenite increases the length of time it takes a cell to transit each phase of the cell cycle).…”

supporting

confidence: 90%

“…Arsenite (5 M) is known to induce apoptosis in U937 cells (McCabe et al, 2000). Many studies have been published in support of a G 2 /M phase-specific sensitivity to arsenite-induced apoptosis in this and other cell types (Li and Broome, 1999;Park et al, 2001;Halicka et al, 2002;Ling et al, 2002;States et al, 2002;Cai et al, 2003). Given the induction of mitotic arrest seen with arsenite treatment, we further investigated the cell cycle phase specificity of the apoptotic response.…”

Section: Resultsmentioning

confidence: 93%

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Arsenite Delays Progression through Each Cell Cycle Phase and Induces Apoptosis following G₂/M Arrest in U937 Myeloid Leukemia Cells

McCollum¹,

Keng²,

States³

et al. 2005

J Pharmacol Exp Ther

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Arsenic is a well known toxicant and carcinogen that is also effective as a chemotherapeutic in the treatment of acute promyelocytic leukemia. Although its effects on humans are well documented, arsenic's mechanism of action is not well understood. Its ability to act as a carcinogen and as a chemotherapeutic seems paradoxical. However, cancer cell transformation and cancer cell destruction can both occur through perturbations of the cell cycle machinery, making cell cycle function a likely target of arsenic action. Arsenic has previously been shown to inhibit cancer cell cycle progression, but the targeted cell cycle phase has been debated. This study was designed to identify the cell cycle phase at which U937 cells are most sensitive to arsenite-induced growth inhibition. Centrifugal elutriation was used to divide asynchronous cell cultures into specific cell cycle phase-enriched fractions. These fractions were monitored for cell cycle phase progression in the presence and absence of sodium arsenite. We found an overall reduction in cell cycle progression rather than induction of arrest at one specific checkpoint. G 2 /M is the phase most sensitive to arsenite-induced apoptosis. However, arsenite profoundly affects U937 cell growth by increasing the length of time it takes cells to transit each phase of the cell cycle. Future study of cell cycle inhibition by arsenic should consider that the effect may not be mediated by the major cell cycle checkpoints.

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confidence: 90%

Section: Resultsmentioning

confidence: 93%

Arsenite Delays Progression through Each Cell Cycle Phase and Induces Apoptosis following G₂/M Arrest in U937 Myeloid Leukemia Cells

McCollum¹,

Keng²,

States³

et al. 2005

J Pharmacol Exp Ther

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“…Our previous studies and those of others have demonstrated that arsenite-induced apoptosis is associated with arrest in mitosis (States et al, 2002;Taylor et al, 2006;McCollum et al, 2003;Huang et al, 2000;Ling et al, 2002). Therefore, we examined cell cycle distribution with flow cytometry and mitotic index analysis.…”

Section: Discussionmentioning

confidence: 91%

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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“…Arsenite is a mitotic disruptor causing mitotic arrest and subsequent apoptosis in SV40-transformed human fibroblast (States et al, 2002), TR9-7 cells , HeLa, KB (Huang and Lee, 1998), CGL-2 (Yih et al, 2005), and U937 (McCabe, Jr. et al, 2000;McCollum et al, 2005) cells. The mechanism through which arsenite causes mitotic arrest is highly disputed.…”

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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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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Arsenite Disrupts Mitosis and Induces Apoptosis in SV40-Transformed Human Skin Fibroblasts

Cited by 50 publications

References 26 publications

Arsenite Delays Progression through Each Cell Cycle Phase and Induces Apoptosis following G₂/M Arrest in U937 Myeloid Leukemia Cells

Arsenite Delays Progression through Each Cell Cycle Phase and Induces Apoptosis following G₂/M Arrest in U937 Myeloid Leukemia Cells

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

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

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Arsenite Disrupts Mitosis and Induces Apoptosis in SV40-Transformed Human Skin Fibroblasts

Cited by 50 publications

References 26 publications

Arsenite Delays Progression through Each Cell Cycle Phase and Induces Apoptosis following G2/M Arrest in U937 Myeloid Leukemia Cells

Arsenite Delays Progression through Each Cell Cycle Phase and Induces Apoptosis following G2/M Arrest in U937 Myeloid Leukemia Cells

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

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

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Arsenite Delays Progression through Each Cell Cycle Phase and Induces Apoptosis following G₂/M Arrest in U937 Myeloid Leukemia Cells

Arsenite Delays Progression through Each Cell Cycle Phase and Induces Apoptosis following G₂/M Arrest in U937 Myeloid Leukemia Cells