Antipsychotic drugs elicit cytotoxicity in glioblastoma multiforme in a calcium-dependent, non-D 2 receptor-dependent, manner

• Published in: Pharmacology research & perspectives Vol. 9; no. 3; p. e00689
• Main Authors: Weissenrieder, Jillian S, Reed, Jessie L, Moldovan, George-Lucian, Johnson, Martin T, Trebak, Mohamed, Neighbors, Jeffrey D, Mailman, Richard B, Hohl, Raymond J
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01-05-2021
• Subjects: Antipsychotic Agents - pharmacology; Antipsychotics; Brain cancer; Calcium Signaling - drug effects; Cancer; Cell Line, Tumor; Cell Survival - drug effects; Central Nervous System Neoplasms - drug therapy; Central Nervous System Neoplasms - metabolism; Cytotoxicity; Dopamine; Dopamine Agonists - pharmacology; Dopamine D2 Receptor Antagonists - pharmacology; Experiments; FDA approval; Flow cytometry; Glioblastoma - drug therapy; Glioblastoma - metabolism; Humans; Pharmaceuticals; Pharmacodynamics; Pharmacology; Psychotropic drugs; Receptors, Dopamine D2 - agonists; Receptors, Dopamine D2 - genetics; United States > US; antipsychotic; glioblastoma; dopamine; calcium signaling
• ISSN: 2052-1707; 2052-1707
• DOI: 10.1002/prp2.689

Dopamine D
-like receptor antagonists have been suggested as being potential anticancer therapeutics with specific utility for central nervous system cancers due to their ability to cross the blood-brain barrier. Despite a plethora of data reporting anticancer effects for D
R antagonists in cell or animal studies, the ligand concentrations or doses required to achieve such effects greatly exceed the levels known to cause high degrees of occupancy of the D
receptor. To resolve this conundrum, we interrogated a panel of glioblastoma multiforme (GBM) cell lines using D
antagonists of varying chemotype. We studied the cytotoxic effects of these compounds, and also ascertained the expression of D
receptors (D
R) on these cells. Although several chemotypes of D
R antagonists, including phenothiazines and phenylbutylpiperidines, were effective against GBM cell line cultures, the highly selective antagonist remoxipride had no anticancer activity at biologically relevant concentrations. Moreover the D
R antagonist-induced cytotoxicity in monolayer cultures was independent of whether the cells expressed D
R. Instead, cytotoxicity was associated with a rapid, high-magnitude calcium flux into the cytoplasm and mitochondria, which then induced depolarization and apoptosis. Blocking this flux protected the GBM cell lines U87MG, U251MG, and A172. Together, these data suggest that the cytotoxicity of these D
R antagonists involves calcium signaling mechanisms, not D
R antagonism. Repurposing of existing drugs should focus on the former, not latter, mechanism.