Naphthalimide derivative attenuates tumor growth of wild-type p53–expressing U87 glioma cells in vitro and in vivo through a biphasic dose-dependent mechanism: A switch from cell cycle to apoptosis

Abstract

Glioblastoma multiforme (GBM) is among the most lethal and recurrent malignant solid tumors. Compound 5 is a naphthalimide derivative that has rarely been investigated for glioma treatment. Therefore, we aimed to determine whether compound 5 exhibits anti-glioma activity. The results revealed that compound 5 reduced the cell viability of U87 glioma cells in a concentration-dependent manner. At lower concentrations, compound 5 arrested the G0/G1 phase through p21 upregulation, and at higher concentrations, it arrested the G2/M phase and induced marked apoptosis through p21 downregulation and p53 upregulation and stabilization. Additionally, compound 5 reduced CDK2 expression at lower concentrations but not at higher concentrations, suggesting that CDK2 plays a key role in the entry into the S phase in U87 glioma cells. At higher concentrations, compound 5 also accumulated cyclin B1 and CDK1, which may contribute to mitotic arrest and subsequent apoptosis. Moreover, compound 5 reduced the levels of antiapoptotic Bcl-w and Mcl-1 proteins, as well as those of inhibitors of apoptosis XIAP and survivin, enhancing compound 5–medicated apoptosis. In an in vivo study, compound 5 reduced tumor growth in a mouse xenograft tumor model. This study is the first to demonstrate that compound 5 inhibits the growth of U87 glioma cells in vitro and in vivo through a biphasic dose–dependent switch from cell cycle arrest to apoptosis in a p21 level–dependent manner. These findings suggest that naphthalimide-based compounds can serve as lead compounds for designing new and more potent anti-glioma drugs.