Targeted therapy based on p53 reactivation reduces both glioblastoma cell growth and resistance to temozolomide

Glioblastoma (GB) is the most common and aggressive malignant tumor of the central nervous system. Despite current intensive treatment regimens, consisting of surgical resection followed by radiotherapy with concomitant andadjuvanttemozolomide(TMZ)chemotherapy,theprognosis of patients with GB remains extremely poor. Considering that alterations of the p53 tumor suppressor pathway have a key role in both GB development and resistance to TMZ treatment, the re-activation of p53 could be an effective therapeutic approach against GB. In this study, we challenged p53 wild-type and mutant GB cell lines with RITA, a molecule originally identified for its ability to restore p53 functions, although it was subsequently shown to act also through p53-independent mechanisms. We examined the effects of RITA on GB cell viability, through MTS and clonogenic assays, and analyzed cell death through cytoflourimetric analyses. In all the tested GB cell lines, RITA significantly reduced the cell proliferative and clonogenic potential and induced cell accumulation in the S and/or G2/M cell cycle phases and massive p53-dependent apoptosis. Moreover, RITA was more effective than the well-known p53 re-activating molecule, nutlin-3, and did not affect the viability of normal astrocytes. In addition, RITA decreased survivin expression and induced DNA damage, two mechanisms that likely contribute to its anti-tumor effects. Furthermore, RITA synergized with TMZ and was able to decrease the expression of MGMT, which is a crucial player in TMZ resistance. Thus, although further studies are warranted to clarify the exact mechanisms of action of RITA, the data of this study suggest the potential of such an approach for GB therapy, which may also help to overcome resistance to TMZ