Abstract
Glioblastoma multiforme (GBM) is one of the most aggressive human tumors with poor survival. Current standard treatment includes chemotherapy with DNA-alkylating agent temozolomide (TMZ), but the acquisition of resistance is a persistent clinical problem limiting the successful treatment of GBM. In our study, we assessed whether nitroxoline has antiproliferative properties against TMZ-resistant cancer cell lines in vitro and in vivo using TMZ-resistant glioblastoma mouse model. Here, we prepared TMZ-resistant cancer cell lines and showed antiproliferative effect of nitroxoline by cytotoxic, migration and clonogenic assay. Anti-proliferative effect of nitroxoline was associated with G0-G1 arrest determined by fluorescence-activated cell sorting (FACS) which ultimately leads to decreased in protein levels of cyclin D1, phosphorylated Rb and cyclin A. In addition, nitroxoline treated cells showed apoptosis confirmed by increased expression of cleaved caspase-3 and cleaved poly ADP-ribose polymerase (PARP). Furthermore, nitroxoline slow down the tumor progression in TMZ-resistant GBM mouse model confirmed by T2WI-MRI, in contrast tumor was significantly increased in non-treated mice. In terms of DWI, we also observed the increased apparent diffusion coefficient (ADC) value, suggestive of decreased cellularity, in nitroxoline treated GBM in mice model, while significantly decreased in non-treated. These results suggest the potential role of nitroxoline for therapeutic development against TMZ-resistant GBM.