D. Goukassian et al., Inhibition of the cyclin D1/E2F pathway by PCA-4230, a potent repressor ofcellular proliferation, BR J PHARM, 132(7), 2001, pp. 1597-1605
1 Tight control of cellular growth is essential to ensure normal tissue pat
terning and prevent pathological responses. Excessive vascular smooth muscl
e cell (VSMC) proliferation is associated with the pathophysiology of ather
osclerosis and restenosis post-angioplasty. Thus, drug targeting of patholo
gical VSMC growth may be a suitable therapeutic intervention.in vascular pr
oliferative diseases.
2 In the present study, we investigated the mechanisms underlying VSMC grow
th arrest induced by the pharmacological agent PCA-4230. Addition of PCA-42
30 to cultured VSMCs blocked the induction of cyclin D1 and cyclin A expres
sion normally seen in serum-restimulated cells. Moreover, PCA-4230 inhibite
d cyclin-dependent kinase 2 (CDK2) activity and abrogated hyperphosphorylat
ion of the retinoblastoma (Rb) gene product. Similarly, PCA-4230-dependent
growth arrest of transformed cell lines correlated with reduced level of cy
clin D1 protein and inhibition of CDK2 activity. Consistent with these find
ings, PCA-4230 repressed serum-inducible cyclin A promoter activity, and ov
erexpression of either cyclin D1 or E2F1 efficiently circumvented this inhi
bitory effect. Importantly, adenovirus-mediated overexpression of E2F1 rest
ored S-phase entry in PCA-4230-treated VSMCs, demonstrating that PCA-4230 r
epresses cyclin A gene expression and VSMC growth via inhibition of the cyc
lin D1/E2F pathway.
3 Because of its ability to inhibit the growth of human VSMCs and transform
ed cell lines, future studies are warranted to assess whether PCA-4230 may
be a suitable therapeutic intervention for the treatment of hyperproliferat
ive disorders, including cardiovascular disease and cancer.