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 that 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 that arsenite-resistant SK-Mel-28 cells did not accumulate less arsenic than arsenite-sensitive A375 cells, suggesting that resistance was not attributable to reduced arsenic accumulation but rather to intrinsic properties of resistant cell lines. The mode of arsenite-induced 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 that induction of mitotic arrest occurs at lower intracellular arsenic concentrations. Higher intracellular arsenic levels induced cell cycle arrest in the S-phase and G2-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 that arsenite has potential for treatment of solid tumors but a functional spindle checkpoint is a prerequisite for a positive response to its clinical application.
|Number of pages||10|
|Journal||Toxicology and Applied Pharmacology|
|State||Published - Jun 1 2008|
Bibliographical noteFunding Information:
This work was supported in part by USPHS grants R01ES011314, P30ES014443, T32ES011564 and P30ES001247, and the University of Louisville Center for Regulatory and Environmental Analytical Metabolomics (CREAM), established with an NSF grant #EPS-044747 to T. Fan. We also thank Ms. Teresa Cassel for assistance in the ICP-MS analysis and Dr. LaCreis Kidd for assistance with the statistical analysis of the ICP-MS data. Portions of this work constituted partial fulfillment for the Ph.D. in Pharmacology and Toxicology awarded to Samuel C. McNeely from the University of Louisville.
- Mitotic arrest
- Spindle checkpoint
ASJC Scopus subject areas