In vitro and in vivo anti-tumor effects of brexpiprazole, a newly-developed serotonin-dopamine activity modulator with an improved safety profile

Shuhei Suzuki,Keita Togashi,Masashi Okada,Tomomi Sanomachi,Masahiro Yamamoto,Chifumi Kitanaka,Asuka Sugai,Shizuka Seino,Takashi Yoshioka

doi:10.18632/oncotarget.26949

Abstract

ABSTRACTFrom the perspective of psycho-oncology, antipsychotics are widely used for patients with cancer. Although some antipsychotic drugs have anti-tumor effects, these antipsychotic drugs are not applicable for cancer patients because of their severe side effects. Brexpiprazole, a novel serotonin-dopamine modulator with an improved side effect profile, was developed as a drug that is structurally and pharmacologically related to aripiprazole, which was reported to have anti-cancer effects. However, it remains unknown whether brexpiprazole has anti-cancer effects. In this study, we examined whether brexpiprazole has anti-tumor effects in cancer cells and cancer stem cells (CSCs) of glioblastoma, pancreatic cancer, and lung cancer. Brexpiprazole suppressed cell growth and induced cell death in the cancer cells and the CSCs, and decreased the CSC properties of the CSCs. Brexpiprazole did not exert any cytotoxic effects on non-cancer cells at the anti-cancer effect-inducing concentration. In the cancer cells and the CSCs, brexpiprazole reduced the expression of survivin, an anti-apoptotic protein, whose reduction sensitizes tumor cells to chemotherapeutic reagents. In the preclinical model in which pancreatic CSCs were subcutaneously implanted into nude mice, brexpiprazole suppressed tumor growth, in addition to reducing the expression of Sox2, a marker for CSCs, and survivin. This suggests that brexpiprazole is a promising antipsychotic drug with anti-tumor effects and an improved safety profile.

Highlights

Cancer is one of the leading causes of death [1]
We examined the toxicity of brexpiprazole in non-cancer cells
Brexpiprazole was not toxic to the normal cells at the examined concentrations (Figure 1C). These results suggest that brexpiprazole is not toxic to normal cells, but has cancer cell- and cancer stem cells (CSCs)-specific cytotoxic and growth-inhibitory effects

Summary

Introduction

Cancer is one of the leading causes of death [1]. As cancer patients are forced to endure poor clinical courses, at least 25–30% of patients with cancer have psychological problems, including depression, anxiety, stress-related syndromes, adjustment disorders, sleep disorders, and delirium [2]. Aripiprazole, a dopamine partial agonist, is used for the management of delirium and emesis in cancer patients [7,8,9], and olanzapine, a multi-acting receptor-targeting antipsychotic drug, is given as an anti-emetic drug for chemotherapy-induced nausea and vomiting [10,11,12]. We previously reported the anti-cancer effects of aripiprazole and olanzapine, which are used for cancer patients with fewer side effects [24, 25]. Olanzapine sometimes causes intolerable sedation [12] and aripiprazole causes akathisia [26, 27]; antipsychotic drugs that have anti-cancer effects with an improved side effect profile are required

Methods

Results

Conclusion