1,25-dihydroxycholecalciferol (1,25-D-3) inhibits the growth of squamous cell carcinoma and down-modulates p21(Waf1/Cip1) in vitro and in vivo

1,25-Dihydroxycholecalciferol (1,25-D-3) has significant antitumor effects in the murine squamous cell carcinoma (SCC) tumor model in vitro and in viv o. We investigated the basis for this antiproliferative activity and found that, in vitro, 1,25-D-3 administration is associated with altered expressi on of cell cycle regulatory proteins, treatment results in retinoblastoma d ephosphorylation, decreased expression of p21(Waf1/Cip1) (p21) mRNA and pro tein, and increased expression of p27(Kip1) (p27) mRNA and protein. Dexamet hasone, which acts synergistically with 1,25-D-3 to inhibit SCC proliferati on, enhanced 1,25-D-3-induced down-modulation of p21 without affecting. the ability of 1,25-D-3 to increase p27 expression. 1,25-D-3 did not induce cl eavage of poly(ADP-ribose) polymerase. These in vitro data suggest that 1,2 5-D-3 exerts antitumor activity in SCC by perturbing cell cycle progression rather than by inducing apoptosis. In vivo, a 1,25-D-3 treatment regimen t hat results in:a decrease in SCC tumor volume is associated with a statisti cally significant decrease in intratumoral p21 expression. p21 expression i s not changed in tumors isolated from control animals or animals treated wi th a nontherapeutic dose of 1,25-D-3. Intratumoral p27 levels were not modu lated by 1,25-D-3 treatment. Thus, both in vitro and in vivo, 1,25-D-3-medi ated growth inhibition is associated with p21 down-modulation.