Abstract
RU486 (mifepristone), a glucocorticoid and progesterone receptor antagonist, has been reported to exert antiproliferative effects on tumor cells. Experiments were performed to analyze the effects of RU486 on the proliferation of the human neuroblastoma, both in vitro and in vivo, using the human neuroblastoma SK-N-SH cell line. The exposure in vitro of SK-N-SH cells to RU486 revealed a dose-dependent inhibition of 3H-thymidine incorporation due to a rapid but persistent inhibition of MAPKinase activity and ERK phosphorylation. A significant decrease of SK-N-SH cell number was evident after 3, 6, and 9 days of treatment (up to 40% inhibition), without evident cell death. The inhibitory effect exerted by RU486 was not reversed by the treatment of the cells with dexamethasone or progesterone. Moreover, RU486 induced a shift in SK-N-SH cell phenotypes, with an almost complete disappearance of the neuronal-like and a prevalence of the epithelial-like cell subtypes. Finally, the treatment with RU486 of nude mice carrying a SK-N-SH cell xenograft induced a strong inhibition (up to 80%) of tumor growth. These results indicated a clear effect of RU486 on the growth of SK-N-SH neuroblastoma cells that does not seem to be mediated through the classical steroid receptors. RU486 acted mainly on the more aggressive component of the SK-N-SH cell line and its effect in vivo was achieved at a concentration already used to inhibit oocyte implantation.
Highlights
Neuroblastoma is the most common solid extracranial tumor that occurs in a child’s first year of life
We have previously shown that antiproliferative effects of RU486 on the human neuroblastoma SK-N-SH cells in vitro is not blocked by either dexamethasone or progesterone [12], suggesting that mifepristone would exert its antiproliferative action through a mechanism that does not involve classical steroid hormone receptors
These results confirmed and widened our preliminary results showing that RU486 may affect the viability of SKN-SH cells during a 9-day treatment [12]; an effect not reversed by the simultaneous treatment of the cells with equal concentrations of progesterone or dexamethasone
Summary
Neuroblastoma is the most common solid extracranial tumor that occurs in a child’s first year of life. It is more common in boys than in girls, but the basis for this prevalence is unclear. Clinical and biological heterogeneity occurs in the presentation of these tumors. They can be classified into three risk categories: low, intermediate, and high. The prognosis of children with low and intermediate risks are excellent, with a survival rate of up to 90%. Children with high-risk tumors have a poor prognosis and a long-term survival rate of less than 50%. Despite the several treatments available, there are still no good results in children with the most severe type of neuroblastoma [1,2]
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