To understand how human
tumor cells respond to the combined treatment with
nocodazole and high LET radiation, alterations in cell cycle, mitotic disturbances and cell death were investigated in the present study. Human cervix
carcinoma HeLa cells were exposed to
nocodazole for 18 h immediately followed by high LET
iron ion irradiation and displayed a sequence of events leading to
DNA damages, mitotic aberrations, interphase restitution and endocycle as well as cell death. A prolonged mitotic arrest more than 10 h was observed following
nocodazole exposure, no matter the irradiation was present or not. The occurrence of mitotic slippage following the mitotic arrest was only
drug-dependent and the irradiation did not accelerate it. The amount of
polyploidy cells was increased following mitotic slippage. No detectable G(2) or G(1) arrest was observed in cells upon the combined treatment and the cells reentered the cell cycle still harboring unrepaired cellular damages. This premature entry caused an increase of multipolar mitotic spindles and amplification of centrosomes, which gave rise to lagging chromosomal material, failure of cytokinesis and polyploidization. These mitotic disturbances and their outcomes confirmed the incidence of mitotic catastrophe and delayed apoptotic features displayed by TUNEL method after the combined treatment. These results suggest that the addition of high-LET
iron ion irradiation to
nocodazole enhanced mitotic catastrophe and delayed apoptosis in HeLa cells. These might be important cell death mechanisms involved in
tumor cells in response to the treatment of
antimitotic drug combined with high LET radiation.