Al's Comment:
Interesting article. They are correct that the D2R receptor family (also known as DRD2) is very important in many types of cancers, including brain tumors – especially in tumors of the midline and brainstem.
However, they are incorrect when they say there is no useful way to target this. The drug Onc201 is a very selective antagonist to DRD2 and is now in clinical trials for brain tumors. Although it is too early to tell how well it works, I have seen a few remarkable responses to it already. This article talks about trying to repurpose older drugs that are NOT selective.
Disclaimer: The Musella Foundation was an early supporter of Onc201 and we are involved in funding the compassionate use program for this treatment.
Posted on: 04/20/2019
J Pharmacol Exp Ther. 2019 Apr 18. pii: jpet.119.256818. doi: 10.1124/jpet.119.256818. [Epub ahead of print]
Cancer and the dopamine D2 receptor: a pharmacological perspective.
Weissenrieder JS1, Neighbors JD1, Mailman RB1, Hohl RJ2.
Author information:
1. Penn State University College of Medicine.
2. Penn State University College of Medicine rhohl@pennstatehealth.psu.edu.
Abstract
The dopamine D2 receptor (D2R) family is upregulated in many cancers, and tied to stemness, while cancer risk may correlate with dopamine-related disorders such as schizophrenia and Parkinson's disease. D2R antagonists also have anticancer efficacy in cell culture and animal models where they reduce tumor growth, induce autophagy, affect lipid metabolism, and cause apoptosis, among other effects. This has led to the hypothesis that D2R ligands are a novel approach to cancer chemotherapy, a particularly appealing concept because of the large number of approved and experimental drugs of this class. We review the current state of the literature, and the evidence for and against this hypothesis. When the existing literature is evaluated from a pharmacological context, one of the striking findings is that the concentrations needed for cytotoxic effects of D2R antagonists are orders of magnitude higher than their affinity for this receptor. Although additional definitive studies will provide further clarity, our hypothesis is that targeting D2-like dopamine receptors will not yield useful ligands for cancer chemotherapy. SIGNIFICANCE STATEMENT: Here we review the literature on the anticancer effects of dopamine D2-receptor antagonists such as the common anti-pyschotic drugs. During the course of this review we have come to the conclusion that the effects of these drugs in the context of cancers such as glioblastoma, is unlikely to be mediated by the D2-receptor and is instead due to other off target effects of these agents.
The American Society for Pharmacology and Experimental Therapeutics.
PMID: 31000578
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