Visit our Expo - Redox and Inflammation signaling 2012

Session X : Cell death in cancer Poster X, 62
The nucleoside analogue cidofovir suppresses lung metastasis and induces apoptosis in
FGF2-overexpressing endothelial cells.
Sandra Liekens*, Sofie Gijsbers*, Erik De Clercq*, Erik Verbeken§, and Sigrid Hatse*
*Rega Institute for Medical Research, Minderbroedersstraat 10, B-3000 Leuven,
Belgium and §Division of Histopathology, K.U.Leuven. E-mail:
Sandra.liekens@rega.kuleuven.be
Cidofovir [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine, (S)-HPMPC] is an
antiviral drug that is clinically used for the treatment of cytomegalovirus retinitis in AIDS
patients (1). Cidofovir also possesses potent activity against human papillomavirus-induced
tumors in animal models and patients (1). We have recently shown that cidofovir inhibits the
development of vascular tumors induced by basic fibroblast growth factor (FGF2)overexpressing
endothelial (3F2T) cells in mice (2). Here, we demonstrate that the cytotoxic
activity of cidofovir in 3F2T cells may result from the specific induction of apoptosis. Cell
cycle analysis revealed that cidofovir induces accumulation of cells in the S phase and, upon
prolonged treatment, a significant increase in sub-G1 cells, exhibiting a sub-diploid DNA
content. Moreover, annexin V binding, an early event in apoptosis induction, was increased in
cidofovir-treated 3F2T cells. Cidofovir also caused nuclear fragmentation and the activation
of caspase-3-like proteases in 3F2T cells, as evidenced by the cleavage of poly(ADPribose)polymerase.
In addition, cidofovir treatment resulted in a pronounced up-regulation of
p53 protein. Protein kinase B/Akt is recognized as a principal mediator of survival signals that
protect cells from undergoing apoptosis. Cidofovir did not suppress the phosphorylation of
Akt nor its downstream regulator Bad, indicating that the Akt pathway is not affected by
cidofovir treatment of 3F2T cells. However, cidofovir inhibited the expression of FGF2 and
FGF2 signaling through Erk42/44, as shown by Western blot analysis. In vivo, cidofovir
markedly suppressed the development of experimental lung metastasis, induced by
inoculation of 3F2T cells in the tail vein of SCID mice. Our results indicate that cidofovir
may inhibit the growth of 3F2T cells via inhibition of FGF2 expression and signaling, and via
the induction of apoptosis through the caspase-3 pathway.
1. De Clercq and Holy (2005) Nat Rev Drug Discov. 4: 928-940.
2. Liekens et al. (2001) Cancer Res. 61: 5057-5064.
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