Data from The DRD2 antagonist haloperidol mediates autophagy-induced ferroptosis to increase temozolomide sensitivity by promoting endoplasmic reticulum stress in glioblastoma

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