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

Frontiers in Oncology

Oncology

Soumitra Guin¹  Marvin J. Meyers¹  Damian J. Krysan²  Michael D. Henry³  Marion Vanneste³  Anita Venzke³  Sarah R. Beattie⁴  Andrew J. Fuller⁴  Andrew J. Jezewski⁴ 

[1] Department of Chemistry, Saint Louis University, Saint Louis, MO, United States;Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City IA, United States;Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA, United States;Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA, United States;Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City IA, United States;Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, United States;Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA, United States;

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

DOI  :  10.3389/fonc.2023.1295185

 received in 2023-09-15, accepted in 2023-10-02,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionAn 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.MethodsIn 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).ResultsCWHM-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. DiscussionAltogether, 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

【 授权许可】

Unknown   
Copyright © 2023 Vanneste, Venzke, Guin, Fuller, Jezewski, Beattie, Krysan, Meyers and Henry