Biology Reference
In-Depth Information
16.4 Cell Cycle Arrest is a Consequence
of Zidovudine Exposure
Inhibition of cells to enter mitosis is a measure of the potential of damage inflicted
on the cell. Impairment of compliance with a cell cycle is one of the consequences
of DNA damage that reflects the inability of the cell to accomplish basic biological
processes.
Cell cycle delay induced by Zidovudine has been reported by Wu et al. in a
human chronic myeloid leukemia cell line (Wu et al.
2004
) and in HL60 cells,
(Roskrow and Wickramasinghe
1990
). Others (Heagy et al.
1991
; Viora et al.
1997
) showed decrease in proliferative response to phytohemagglutinins and delay
in S-phase in peripheral blood mononuclear cells and human leukemic CEM cells.
A cytostatic effect in human colon carcinoma WiDr cells was induced at 12 h,
peaking at 24 h, and reversed to baseline at 72 h (Chandrasekaran et al.
1995
). The
authors then proposed that AZT-induced cytostasis is a transient and reversible
effect, adding that similar results were observed in 8/9 tumor cell lines examined.
A correlation between changes in the gene expression of cell cycle-related genes
and S-phase arrest was demonstrated in HeLa cells (Olivero et al.
2005
). In
experiments carried out using different microarray platforms, the authors examined
the correlation of up-/downregulation of some key genes in cell cycle G
1
/S
progression and S-phase accumulation in cells exposed to the combination
Zidovudine-Lamivudine (2',3'-dideoxy-3'-thiacytidine) for 24 h. Changes in gene
expression suggested that the cyclin-D-Rb pathway could be mediating the cell
cycle arrest (Olivero et al.
2005
). A synchrony between cell cycle and centrosomal
cycle should exist to warrant proper cell division and cell homeostasis. However,
when cell cycle distortions take place the centrosomal division could progress
asynchronically causing centrosomal amplification.
16.5 Zidovudine Acts as a Centrosome Disruptor
Employing immunohistochemistry, Borojerdi et al. (
2009
) explored the ability of
Zidovudine to act as a centrosome disruptor. The authors used hamster CHO cells and
human NHMEC strains, exposed to Zidovudine for 24 h and showed centrosomal
disruption evidenced by pericentrin signaling. Additionally, they demonstrated
aberrations in tubulin polymerization in cells bearing abnormal centrosomes.
A typical consequence of these abnormalities is chromosomal instability and
aneuploidy. The missegregation of chromosomes to the daughter cells was docu-
mented by scoring kinetochore positive micronuclei (Borojerdi et al.
2009
).
An increase in the presence of aberrant cells, including multipolar metaphases/
anaphases and cells bearing lagging chromosomes was observed in correlation with
increasing doses of Zidovudine in CHO cells. When compared to untreated CHO
cells, Zidovudine-exposed cells showed an increase in the number of pericentrin
