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

Abstract

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

Intake of oligoelements with cytarabine or etoposide alters dopamine levels and oxidative damage in rat brain

“…In fact, previous studies suggest that dopamine receptors may serve as a biomarker for diverse malignancies 46 . Although novel analogues may improve the potential to repurpose this class of drugs to treat brain tumors and/or brain metastasis 47 . Finally, is important knowledge that dopamine changes in brain regions could have implications for motor control, modulation of affective and emotional states, reward mechanisms, reinforcement of behavior, and selected higher cognitive functions 48 .…”