Dopamine D2 Receptor Antagonists as Potential Therapeutics for Glioblastoma Multiforme

Restricted (Penn State Only)
Author:
Weissenrieder, Jillian
Graduate Program:
Biomedical Sciences
Degree:
Doctor of Philosophy
Document Type:
Dissertation
Date of Defense:
March 04, 2019
Committee Members:
  • Raymond J. Hohl, Dissertation Advisor
  • Jeffrey D Neighbors, Committee Chair
  • Kent Eugene Vrana, Committee Member
  • David James Degraff, Committee Member
  • Xuemei Huang, Outside Member
Keywords:
  • cancer
  • pharmacology
  • dopamine D2 receptor
  • antipsychotic
  • thioridazine
  • glioblastoma
Abstract:
Recent reports have suggested that dopamine D2 receptor antagonists may have potential to be repurposed as anticancer therapeutics. These compounds, including the phenothiazine chemotype and others, have a long history as therapeutics and some are approved in the US as antipsychotics in patients with schizophrenia. Thus, they have well-known pharmacokinetic, pharmacodynamic, and safety profiles that position them well for repurposing for other indications, such as anticancer treatment. While much is known about their safety and efficacy in the context of schizophrenia, little is known about their mechanism of action as anticancer agents. There is a great disparity in compound affinity for the D2 (and D2-like) receptors and anticancer efficacy. Thus, we hypothesized that the anticancer activity of these compounds was due to an “off-target” effect, not direct action at the D2 receptor. Indeed, though these compounds have broad cytotoxicity in glioblastoma multiforme (GBM) monolayer cultures, these effects both require high, non-D2 selective concentrations and are apparently independent of D2 receptor signaling. We observe a dependence on calcium signaling to elicit this cytotoxicity which may be blocked by calcium chelation with BAPTA-AM (1,2-Bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis (acetoxymethyl ester)). Thus, we conclude that the mechanism for acute cytotoxicity of D2 receptor antagonists may require calcium overload. On the other hand, GBM cells do express functional D2 receptors. The presence of these receptors may affect spheroid formation, a marker of stemness, at more selective concentrations of D2R modulators. This may provide another potential mechanism by which these compounds may provide therapeutic benefit at a lower and perhaps more selective concentration. However, we did not see any changes in stemness markers at these concentrations, only distortions in spheroid-forming behaviors. These findings suggest that other factors, such as metabolism or cell-cell adhesion, are altered in D2-antagonist treated GBM cells to contribute to these spheroid formation phenotypes. Overall, we conclude that D2 receptor antagonists may provide some limited therapeutic efficacy for patients with few treatment options, but that this effect is not due to direct interactions with the D2 receptor.