In this study, we evaluated the activity of two novel pyrazolopyrimidine derivatives (Si 34 and Si 35) against ARO cells, a human anaplastic thyroid cancer cell line. ARO cells exposed to different concentrations of the drugs showed a reduced growth rate and an increase of mortality. After 72 h incubation, doses of 5 and 10 μM of Si 34 determined a decrease of cell counts by ~25% and ~75% compared with those of control cells, respectively. Similar findings were observed using Si 35. Treatment with both Si 34 and Si 35 at 10 μM increased also cell mortality (~29% and ~18%, respectively). At these concentrations, a decrease in cyclin D1 levels was observed. To improve the biopharmaceutical properties, a liposome formulation was prepared. When entrapped in unilamellar liposomes, Si 34 exerted its cytotoxic effects even at lower doses (maximal inhibition at 5 μM) and after shorter incubation time (48 h) either in ARO or other thyroid cancer cell lines. The effects were associated with weak apoptotic death. Inhibition of EGF-stimulated src and ERK phosphorylation, as well as reduction of migration properties of ARO cells was also observed. Moreover, growth of tumor xenografts induced in SCID mice was inhibited by intravenous administration of 25-50 mg/Kg-1 of the drug liposomal formulation. In conclusion, the liposomal preparation of this novel pyrazolopyrimidine derivative appears to be a promising tool for the treatment of anaplasic thyroid cancer.
Cytotoxic effects of a novel pyrazolopyrimidine derivative entrapped in liposomes in anaplastic thyroid cancer cells in vitro and in xenograft tumors in vivo
NAVARRA, Michele;
2008-01-01
Abstract
In this study, we evaluated the activity of two novel pyrazolopyrimidine derivatives (Si 34 and Si 35) against ARO cells, a human anaplastic thyroid cancer cell line. ARO cells exposed to different concentrations of the drugs showed a reduced growth rate and an increase of mortality. After 72 h incubation, doses of 5 and 10 μM of Si 34 determined a decrease of cell counts by ~25% and ~75% compared with those of control cells, respectively. Similar findings were observed using Si 35. Treatment with both Si 34 and Si 35 at 10 μM increased also cell mortality (~29% and ~18%, respectively). At these concentrations, a decrease in cyclin D1 levels was observed. To improve the biopharmaceutical properties, a liposome formulation was prepared. When entrapped in unilamellar liposomes, Si 34 exerted its cytotoxic effects even at lower doses (maximal inhibition at 5 μM) and after shorter incubation time (48 h) either in ARO or other thyroid cancer cell lines. The effects were associated with weak apoptotic death. Inhibition of EGF-stimulated src and ERK phosphorylation, as well as reduction of migration properties of ARO cells was also observed. Moreover, growth of tumor xenografts induced in SCID mice was inhibited by intravenous administration of 25-50 mg/Kg-1 of the drug liposomal formulation. In conclusion, the liposomal preparation of this novel pyrazolopyrimidine derivative appears to be a promising tool for the treatment of anaplasic thyroid cancer.Pubblicazioni consigliate
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