rRNA Synthesis- Inhibiting Drugs in Antineoplastic Therapy: p53 Stabilization Level is Directly Related to the Cell Ribosome Biogenesis Rate

Many drugs utilized in cancer chemotherapy inhibit the ribosome biogenesis process evoking a p53 response, in p53 wild-type tumors, and the level of p53 stabilization may be important for the efficacy of the anticancer treatment. For this reason we studied the degree of p53 stabilization after treatments with rRNA synthesis-inhibiting drugs in relation with the cell ribosomal biogenesis rate, in cancer cell lines with functional p53. We showed that a direct relationship exists between the amount of p53 stabilized after rRNA synthesis inhibition and the ribosome biogenesis level of the cancer cells before the treatment. This was due to different levels of inactivation of the ribosomal proteins-MDM2 pathway of p53 degradation. We also analyzed the relationship between these differences in p53 stabilization and the degree of the induced cytotoxic effects. We found that in cell lines with a high ribosome biogenesis rate the inhibition of rRNA synthesis induced not only the cell cycle arrest, but also the apoptotic cell death. Whereas, the inhibition of rRNA synthesis in cell lines with low level of ribosome biogenesis only caused the cell cycle arrest. The data provided in this thesis suggest that the rRNA synthesis-inhibiting drugs alone should be considered in the treatment of cancers characterized by high levels of ribosome biogenesis but cannot be recommended for the treatment of cancers characterized by low ribosome biogenesis levels. In this type of cancers, in order to obtain a p53 stabilization sufficient to activate the apoptotic death, it might be useful to combine treatments with ribosomal biogenesis inhibitors to drugs that stabilize p53 through a different pathway.