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

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

Front Oncol. 2023 Oct 16:13:1295185. doi: 10.3389/fonc.2023.1295185. eCollection 2023.

Authors

Marion Vanneste^{1

2}, Anita Venzke^{1

2}, Soumitra Guin³, Andrew J Fuller⁴, Andrew J Jezewski⁴, Sarah R Beattie⁴, Damian J Krysan^{1

4

5}, Marvin J Meyers³, Michael D Henry^{1

2}

Affiliations

¹ Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City IA, United States.
² Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, United States.
³ Department of Chemistry, Saint Louis University, Saint Louis, MO, United States.
⁴ Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA, United States.
⁵ Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA, United States.

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.

Keywords: anti-cancer effect; blood-brain barrier; calmodulin; drug repurposing; metastasis; mitotic arrest; phenothiazine.

Abstract

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