Arsenic trioxide arrests cells early in mitosis leading to apoptosis.
Arsenic trioxide (As(2)O(3)) is highly effective in the treatment of acute promyelocytic leukemias that express the promyelocytic leukemia-retinoic acid receptor-alpha (PML-RARalpha) fusion protein. However, evidence has accumulated that As(2)O(3) induces apoptosis regardless of PML-RARalpha status. Here we show that, at clinically relevant concentrations, As(2)O(3) causes S and G(2)M phase arrest of both PML-RARalpha-positive and -negative leukemia cell lines, thus inhibiting their growth. Apoptotic cells are generated predominately from the G(2)M fraction. Using several independent methods, we demonstrate that the cells accumulated in the G(2)M peak consist primarily of cells arrested in the early stages of mitosis, prophase, prometaphase and metaphase. In mitotic cells, there was significant activation of caspases, PARP cleavage, and morphological changes characteristic of apoptosis. Unlike microtubule-active drugs that arrest cells in metaphase, arsenic trioxide did not affect the architecture of microtubules. Our data suggest that the antileukemic activities of arsenic may be a result of mitotic arrest which culminates in apoptosis.
Halicka
H Dorota
HD
Brander Cancer Research Institute, New York Medical College, Hawthorne, New York 10532, USA.
Smolewski
Piotr
P
Darzynkiewicz
Zbigniew
Z
Dai
Wei
W
Traganos
Frank
F
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000627:therapeutic use*; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002455:Cell Division; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D018922:HL-60 Cells; D006801:Humans; D007150:Immunohistochemistry; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy*; D008856:Microscopy, Fluorescence; D008938:Mitosis / Q000187:drug effects*; D010087:Oxides / Q000627:therapeutic use*; D010766:Phosphorylation; D013997:Time Factors; D014407:Tumor Cells, Cultured; D020298:U937 Cells
D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D001973:Bromodeoxyuridine; D000077237:Arsenic Trioxide