Exposure of human lung cancer cells to 8-chloro-adenosine induces G2/M arrest and mitotic catastrophe.
8-Chloro-adenosine (8-Cl-Ado) is a potent chemotherapeutic agent whose cytotoxicity in a variety of tumor cell lines has been widely investigated. However, the molecular mechanisms are uncertain. In this study, we found that exposure of human lung cancer cell lines A549 (p53-wt) and H1299 (p53-depleted) to 8-Cl-Ado induced cell arrest in the G2/M phase, which was accompanied by accumulation of binucleated and polymorphonucleated cells resulting from aberrant mitosis and failed cytokinesis. Western blotting showed the loss of phosphorylated forms of Cdc2 and Cdc25C that allowed progression into mitosis. Furthermore, the increase in Ser10-phosphorylated histone H3-positive cells revealed by fluorescence-activated cell sorting suggested that the agent-targeted cells were able to exit the G2 phase and enter the M phase. Immunocytochemistry showed that microtubule and microfilament arrays were changed in exposed cells, indicating that the dynamic instability of microtubules and microfilaments was lost, which may correlate with mitotic dividing failure. Aberrant mitosis resulted in mitotic catastrophe followed by varying degrees of apoptosis, depending on the cell lines. Thus, 8-Cl-Ado appears to exert its cytotoxicity toward cells in culture by inducing mitotic catastrophe.
Zhang
Hong-Yu
HY
Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Xue Yuan Road 38, Beijing 100083, PR China.
Gu
Yan-Yan
YY
Li
Zeng-Gang
ZG
Jia
Yu-Hong
YH
Yuan
Lan
L
Li
Shu-Yan
SY
An
Guo-Shun
GS
Ni
Ju-Hua
JH
Jia
Hong-Ti
HT
D000241:Adenosine / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008938:Mitosis / Q000187:drug effects*
D006131:Growth Inhibitors; D000241:Adenosine
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