Arsenite‐induced mitotic death is distinct from both nocodazole and Taxol

Abstract

Arsenite causes mitotic arrest and death at anaphase, but the mechanism is highly disputed. We compared arsenite-induced mitotic arrest to mitotic arrest induced by two spindle poisons, nocodazole and Taxol. Mitotic index peaked earlier during nocodazole and Taxol treatments vs. arsenite treatment in TR9-7 cells. Spindle formation occurred in arsenite- and Taxol-treated cells but not in nocodazole-treated cells. Nocodazole-treated mitotic cells always contained two centrosomes. In contrast, many arsenite-treated mitotic cells contained more than two centrosomes. Taxol-induced centrosome duplication was concentration dependent and only occurred at sub-therapeutic doses. We tested additional cell lines to examine if arsenite sensitivity correlated with Taxol and nocodazole. HeLa, A375, and A2780 cells were sensitive to all three drugs. CP70 cells, cisplatin-resistant derivative of A2780 cells, were as sensitive to mitotic arresting drugs as their parental line. A549 cells were sensitive to nocodazole and Taxol, but were resistant to arsenite. Co-treatment with BSO, a glutathione synthase inhibitor, and MK571, an MRP export pump inhibitor, sensitized A549 cells to arsenite but did not alter nocodazole or Taxol sensitivity. In conclusion, arsenite-induced mitotic arrest appears to be independent of direct effects on tubulin polymerization. (Supported by PHS grants R01 ES011314 and F30 ES013372.)