The DRD2 Antagonist Haloperidol Mediates Autophagy-Induced Ferroptosis to Increase Temozolomide Sensitivity by Promoting Endoplasmic Reticulum Stress in Glioblastoma

Abstract

Purpose: Temozolomide resistance remains a major obstacle in and is inversely correlated with temozolomide sensitivity the treatment of glioblastoma (GBM). The combination of temoin GBM. The DRD2 antagonist haloperidol, a butylbenzene zolomide with another agent could offer an improved treatment antipsychotic, markedly induces ferroptosis and effectively option if it could overcome chemoresistance and prevent side enhances temozolomide efficacy in vivo and in vitro. Mechaniseffects. Here, we determined the critical drug that cause ferroptosis tically, haloperidol suppressed the effect of temozolomide in GBM cells and elucidated the possible mechanism by which drug on cAMP by antagonizing DRD2 receptor activity, and the combination overcomes chemoresistance. increases in cAMP/PKA triggered ER stress, which led to Experimental Design: Haloperidol/temozolomide synergism autophagy and ferroptosis. Furthermore, elevated autophagy was assessed in GBM cell lines with different dopamine D2 receptor mediates downregulation of FTH1 expression at the posttrans(DRD2) expression in vitro and in vivo. Inhibitors of ferroptosis, lational level in an autophagy-dependent manner and ultimately autophagy, endoplasmic reticulum (ER) stress and cyclic adenosine leads to ferroptosis. monophosphate (cAMP)/protein kinase A (PKA) were used to Conclusions: Our results provide experimental evidence for validate the specific mechanisms by which haloperidol and temorepurposing haloperidol as an effective adjunct therapy to inhibit zolomide induce ferroptosis in GBM cells. adaptive temozolomide resistance to enhance the efficacy of cheResults: In the present work, we demonstrate that the DRD2 moradiotherapy in GBM, a strategy that may have broad prospects level is increased by temozolomide in a time-dependent manner for clinical application.