Human Glioblastoma Multiforme: p53 Reactivation by a Novel MDM2 Inhibitor
Costa et al. PLoS ONE, 2013, (8) 1-19 Glioblastoma Multiforme (GBM) is the most common and aggressive type of brain tumor found in humans. Prognosis for GBM patients is usually very poor (less than one year survival time after diagnosis), due to chemotherapeutic drug resistance from the tumor. Research has linked GBM to malfunction of the p53 tumor suppressing protein. When bound to overexpressed MDM2, an oncoprotein, p53 is inactivated and unable to inhibit cancer cell development, causing the tumor to grow and spread. This paper will analyze a research article by Costa et al. (2013) that focuses on using an inhibitor of MDM2 called ISA27 to increase p53 activity. The group hypothesized that applying the MDM2 oncoprotein inhibitor ISA27 to Glioblastoma Multiforme cells would stimulate p53 activity, leading to the arrest of the tumor’s growth and induction of apoptosis in the cancerous cells. To test this hypothesis, the group tested ISA27’s effectiveness on GBM cells. Cell lines with GBM tumors that expressed both MDM2 and wild-type p53 were first treated in vitro with ISA27. After allowing the drug to take effect, the cells were analyzed for concentration of active p53 and other signaling proteins that contribute to apoptosis and cell cycle arrest. The experiment was also performed in vivo in nude mice, using ISA27 alone and in combination with another common GMB chemotherapeutic drug, Temozolomide (TMZ). The in vivo testing is significant because the effectiveness of MDM2 inhibitors has not been thoroughly investigated outside of incubated medium, and in combination with other drugs. Analysis of the treated cell lines showed an increase back to normal levels of p53 concentration and activity, thus a negative control effect on the tumor. This means ISA27 was successful