In vitro and in vivo anti-tumor effects of brexpiprazole, a newly-developed serotonin-dopamine activity modulator with an improved safety profile
In vitro and in vivo anti-tumor effects of brexpiprazole, a newly-developed serotonin-dopamine activity modulator with an improved safety profile
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DOI：
10.18632/oncotarget.26949
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发表时间：
2019-05
期刊：
影响因子：
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通讯作者：
Shuhei Suzuki;Masahiro Yamamoto;Keita Togashi;Tomomi Sanomachi;Asuka Sugai;Shizuka Seino;T. Yoshioka;C. Kitanaka;M. Okada
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文献类型：
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作者：
Shuhei Suzuki;Masahiro Yamamoto;Keita Togashi;Tomomi Sanomachi;Asuka Sugai;Shizuka Seino;T. Yoshioka;C. Kitanaka;M. Okada
摘要从精神肿瘤学的角度来看，抗精神病药物被广泛用于癌症患者。虽然一些抗精神病药物具有抗肿瘤作用，但由于副作用严重，这些抗精神病药物不适用于癌症患者。布雷克哌唑是一种新型的5-羟色胺-多巴胺调节剂，具有改善的副作用，是一种结构和药理上与阿立哌唑相关的药物，据报道，阿立哌唑具有抗癌作用。然而，目前还不清楚布雷西哌唑是否具有抗癌作用。在这项研究中，我们研究了布雷克哌唑对胶质母细胞瘤、胰腺癌和肺癌的癌细胞和肿瘤干细胞(CSCs)是否具有抗肿瘤作用。灯盏花素可抑制癌细胞和CSCs的生长和诱导细胞死亡，降低CSCs的CSC特性。在抗癌作用诱导浓度范围内，灯盏花素对非肿瘤细胞无细胞毒作用。在癌细胞和CSCs中，布雷克哌唑减少了Survivin的表达，Survivin是一种抗凋亡蛋白，它的减少使肿瘤细胞对化疗药物敏感。在临床前模型中，胰腺肿瘤干细胞被移植到裸鼠皮下，除了减少肿瘤干细胞的标志物Sox2和Survivin的表达外，布雷西哌唑还抑制了肿瘤的生长。这表明布雷西哌唑是一种很有前途的抗精神病药物，具有抗肿瘤作用，并改善了安全性。
ABSTRACT From 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.