Sertindole inhibits autophagic flux and glioma progression

Abstract

Gliomas, the most lethal brain tumors, often exhibit resistance to conventional chemotherapy and/or radiotherapy. This study reveals that sertindole, a potent dopamine D2 receptor antagonist primarily designed as an antipsychotic medication for schizophrenia, effectively inhibits glioma progression. Our findings demonstrate that sertindole suppresses the proliferation of U251 and U87 tumor cells, impedes cell cycle progression in vitro, and curtails xenograft tumor growth in vivo. Moreover, we present compelling evidence demonstrating the ability of sertindole to enhance the cellular response to the chemotherapeutic agent temozolomide both in vitro and in vivo. Additionally, our findings reveal that sertindole effectively suppresses the self-renewal capacity and expression of stemness-associated genes, such as Nanog and Sox2, in glioma tumor cells and glioma stem cells. A mechanistic investigation demonstrated that sertindole enhances the formation of autophagosome-lysosome complexes while concurrently impeding autophagic flux through the inhibition of lysosomal hydrolytic enzymes CTSD and CTSB, ultimately resulting in decreased growth of tumor cells. In conclusion, our findings suggest that sertindole has the potential to develop into a potent antiglioma therapeutic agent.

A longitudinal single-cell and spatial multiomic atlas of pediatric high-grade glioma

“…Our framework for identifying tumor cell-intrinsic drug targets implicated several mechanisms of therapy resistance and uncovered novel targets. Synaptic electrochemical signaling through multiple receptors has been increasingly implicated in adult and pediatric glioma progression 44 , including acetylcholine [47][48][49] , dopamine [50][51][52] , and GABA [53][54][55] . We found that neuroactive signaling is broadly upregulated in pHGG, suggesting that tumor cells may become increasingly dependent on synaptic activity over time.…”