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

Abstract

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.

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

“…We used two cancer cell lines known to undergo arsenite-induced mitotic arrest and subsequent apoptosis one having functional p53 (melanoma, A375) and and the other phenotypically null p53 (cervical cancer, HeLa) as well as an arsenite-sensitive fibroblast cell line with a tet-off regulated p53 construct (TR9-7). P53 expression has previously been shown to affect the ability of cells to escape from mitotic arrest McNeely et al, 2006). Mitotic structure and protein expression were analyzed in order to identify an alternative mechanism(s) or target(s) unique to arsenite-induced mitotic arrest.…”

Demethylation and alterations in the expression level of the cell cycle–related genes as possible mechanisms in arsenic trioxide–induced cell cycle arrest in human breast cancer cells

“…15 One of the mechanisms that have been proposed through which As 2 O 3 eliminates APL and other cancer cells is the accumulation of cells in the phase of cell cycle and the subsequent mitotic arrest-associated apoptosis or mitotic catastrophe. [26][27][28][29][30] However, the cell cycle regulation mechanism of As 2 O 3 has not yet been clarified, especially in solid tumors. 31 These reports led us to hypothesize that the induction of DNA hypomethylation is one of the molecular mechanisms underlying the As 2 O 3 -promoted cell cycle arrest in breast cancer cells mediated by changes in the expression level of cell cycle-related genes.…”

L-Ascorbic acid and α-Tocopherol to protect against arsenic trioxide induced oxidative stress in H9c2 cardiomyocytes

“…[2] Inorganic arsenic is now a first choice cancer chemotherapeutic against certain leukemia. [3], [4] The US Food and Drug Administration (FDA) approved the use of Trisenox brand arsenic trioxide (As 2 O 3 ) for the treatment of acute promyelocytic leukemia in September 2000. [5] Most APL cases are characterized by a t (15;17) translocation that fuses the promyelocytic leukemia (PML) gene on chromosome 15 to the retinoic acid receptor α (RARα) gene on chromosome 17, resulting in the formation of the oncoprotein promyelocytic leukemia/retinoic acid receptor (PML-RARα) fusion protein.…”