The anti-cancer efficacy of a novel phenothiazine derivative is independent of dopamine and serotonin receptor inhibition

Marion Vanneste; Anita Venzke; Soumitra Guin; Andrew J. Fuller; Andrew J. Jezewski; Sarah R. Beattie; Damian J. Krysan; Marvin J. Meyers; Michael D. Henry

doi:10.3389/fonc.2023.1295185

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The anti-cancer efficacy of a novel phenothiazine derivative is independent of dopamine and serotonin receptor inhibition

Journal article

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The anti-cancer efficacy of a novel phenothiazine derivative is independent of dopamine and serotonin receptor inhibition

Marion Vanneste, Anita Venzke, Soumitra Guin, Andrew J. Fuller, Andrew J. Jezewski, Sarah R. Beattie, Damian J. Krysan, Marvin J. Meyers and Michael D. Henry

Frontiers in oncology, Vol.13, 1295185

10/16/2023

DOI: 10.3389/fonc.2023.1295185

PMCID: PMC10613967

PMID: 37909019

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Abstract

Introduction: An attractive, yet unrealized, goal in cancer therapy is repurposing psychiatric drugs that can readily penetrate the blood-brain barrier for the treatment of primary brain tumors and brain metastases. Phenothiazines (PTZs) have demonstrated anti-cancer properties through a variety of mechanisms. However, it remains unclear whether these effects are entirely separate from their activity as dopamine and serotonin receptor (DR/5-HTR) antagonists. Methods: In this study, we evaluated the anti-cancer efficacy of a novel PTZ analog, CWHM-974, that was shown to be 100-1000-fold less potent against DR/5-HTR than its analog fluphenazine (FLU). Results: CWHM-974 was more potent than FLU against a panel of cancer cell lines, thus clearly demonstrating that its anti-cancer effects were independent of DR/5-HTR signaling. Our results further suggested that calmodulin (CaM) binding may be necessary, but not sufficient, to explain the anti-cancer effects of CWHM-974. While both FLU and CWHM-974 induced apoptosis, they induced distinct effects on the cell cycle (G0/G1 and mitotic arrest respectively) suggesting that they may have differential effects on CaM-binding proteins involved in cell cycle regulation. Discussion: Altogether, our findings indicated that the anti-cancer efficacy of the CWHM-974 is separable from DR/5-HTR antagonism. Thus, reducing the toxicity associated with phenothiazines related to DR/5-HTR antagonism may improve the potential to repurpose this class of drugs to treat brain tumors and/or brain metastasis

Oncology

Details

Title: Subtitle: The anti-cancer efficacy of a novel phenothiazine derivative is independent of dopamine and serotonin receptor inhibition
Creators: Marion Vanneste - University of Iowa
Anita Venzke - University of Iowa
Soumitra Guin - Saint Louis University
Andrew J. Fuller - University of Iowa
Andrew J. Jezewski - University of Iowa
Sarah R. Beattie - University of Iowa
Damian J. Krysan - University of Iowa
Marvin J. Meyers - Saint Louis University
Michael D. Henry - University of Iowa
Resource Type: Journal article
Publication Details: Frontiers in oncology, Vol.13, 1295185
DOI: 10.3389/fonc.2023.1295185
PMID: 37909019
PMCID: PMC10613967
NLM abbreviation: Front Oncol
ISSN: 2234-943X
eISSN: 2234-943X
Publisher: Frontiers Media S.A
Language: English
Date published: 10/16/2023
Academic Unit: Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Pathology; Radiation Oncology; Infectious Disease (Pediatrics); Internal Medicine
Record Identifier: 9984501760202771

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