Therapeutic potential of pentamidine for glioma‐initiating cells and glioma cells through multimodal antitumor effects

Abstract

AbstractGlioma‐initiating cells, which comprise a heterogeneous population of glioblastomas, contribute to resistance against aggressive chemoradiotherapy. Using drug reposition, we investigated a therapeutic drug for glioma‐initiating cells. Drug screening was undertaken to select candidate agents that inhibit proliferation of two different glioma‐initiating cells lines. The alteration of proliferation and stemness of the two glioma‐initiating cell lines, and proliferation, migration, cell cycle, and survival of these two differentiated glioma‐initiating cell lines and three different glioblastoma cell lines treated with the candidate agent were evaluated. We also used a xenograft glioma mouse model to evaluate anticancer effects of treated glioma cell lines. Among the 1301 agents, pentamidine—an antibiotic for Pneumocystis jirovecii—emerged as a successful antiglioma agent. Pentamidine treatment suppressed proliferation and stemness in glioma‐initiating cell lines. Proliferation and migration were inhibited in all differentiated glioma‐initiating cells and glioblastoma cell lines, with cell cycle arrest and caspase‐dependent apoptosis induction. The in vivo study reproduced the same findings as the in vitro studies. Pentamidine showed a stronger antiproliferative effect on glioma‐initiating cells than on differentiated cells. Western blot analysis revealed pentamidine inhibited phosphorylation of signal transducer and activator of transcription 3 in all cell lines, whereas Akt expression was suppressed in glioma‐initiating cells but not in differentiated lines. In the present study, we identified pentamidine as a potential therapeutic drug for glioma. Pentamidine could be promising for the treatment of glioblastomas by targeting both glioma‐initiating cells and differentiated cells through its multifaceted antiglioma effects.