Arsenic targets tubulins to induce apoptosis in myeloid leukemia cells.
Arsenic exhibits a differential toxicity to cancer cells. At a high concentration (>5 microM), As2O3 causes acute necrosis in various cell lines. At a lower concentration (0.5-5 microm), 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.
Li
Y M
YM
Department of Laboratories, North Shore University Hospital, Manhasset, New York 11030, USA. YMLI@AOL.COM
Broome
J D
JD
D017209:Apoptosis / Q000187:drug effects*; D001151:Arsenic / Q000494:pharmacology*; D001665:Binding Sites; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D007951:Leukemia, Myeloid / Q000473:pathology*; D008938:Mitosis / Q000187:drug effects; D014404:Tubulin / Q000187:drug effects* / Q000378:metabolism
D014404:Tubulin; D006160:Guanosine Triphosphate; D001151:Arsenic