Arsenic targets tubulins to induce apoptosis in myeloid leukemia cells

Arsenic exhibits a differential toxicity to cancer cells, At a high concentration (>5 pM), As2O3 causes acute necrosis in various cell lines, At a lower concentration (0.5-5 mu M), it induces myeloid cell maturation and an arrest in metaphase, leading to apoptosis, As2O3-treated cells have features found with both tubulin-assembling enhancers (Taxol) and inhibitors (colchicine), Prior treatment of monomeric tubulin with As2O3 markedly inhibits GTP-induced polymerization and microtubule formation in vitro but does not destabilize GTP-induced tubulin polymers. Cross-inhibition experiments indicate that As2O3 is a noncompetitive inhibitor of GTP binding to tubulin, These observations correlate with the three-dimensional structure of beta-tubulin and suggest that the cross-linking of two vicinal cysteine residues (Cys-12 and Cys-213) by trivalent arsenic inactivates the GTP binding site, Furthermore, exogenous GTP can prevent As2O3-induced mitotic arrest.