Brexpiprazole, a Serotonin-Dopamine Activity Modulator, Can Sensitize Glioma Stem Cells to Osimertinib, a Third-Generation EGFR-TKI, via Survivin Reduction
Brexpiprazole, a Serotonin-Dopamine Activity Modulator, Can Sensitize Glioma Stem Cells to Osimertinib, a Third-Generation EGFR-TKI, via Survivin Reduction
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DOI：
10.3390/cancers11070947
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发表时间：
2019-06-26
期刊：
影响因子：
5.2
通讯作者：
Okada, Masashi
中科院分区：
文献类型：
--
作者：
Suzuki, Shuhei;Yamamoto, Masahiro;Okada, Masashi
胶质母细胞瘤是一种原发性脑肿瘤，由于其高化疗耐药能力，预后不良。肿瘤干细胞（CSCs）是化疗耐药的机制之一。尽管靶向CSC的治疗是有希望的，但靶向CSC的策略仍然不成功。由于表皮生长因子受体（EGFR）基因的扩增、突变或两者共同导致的EGFR异常激活在胶质母细胞瘤中很常见。然而，胶质母细胞瘤对EGFR酪氨酸激酶抑制剂（EGFR-TKI）具有耐药性，克服耐药性至关重要。Brexpipazole是一种新的，安全的多巴胺-多巴胺活性调节剂，用于精神分裂症和抑郁症，最近报道具有抗CSC活性和作为化疗增敏剂的功能。在这里，我们研究了它对奥希替尼的化学增敏作用，奥希替尼是第三代EGFR-TKI，具有良好的安全性，在胶质瘤干细胞（GSC）中，这是胶质母细胞瘤的CSC。布立哌唑治疗使GSC对奥希替尼敏感，并减少抗凋亡因子生存素的表达，并且生存素的药理学和遗传抑制作用模拟了布立哌唑的作用。此外，与单独使用任何一种药物相比，联合使用布雷哌唑和奥希替尼更有效地抑制肿瘤生长，体内无明显毒性。这表明，布雷哌唑和奥希替尼的组合是通过下调生存素表达使GSC化学增敏的胶质母细胞瘤的潜在治疗策略。
Glioblastoma is a primary brain tumor associated with a poor prognosis due to its high chemoresistance capacity. Cancer stem cells (CSCs) are one of the mechanisms of chemoresistance. Although therapy targeting CSCs is promising, strategies targeting CSCs remain unsuccessful. Abnormal activation of epidermal growth factor receptors (EGFRs) due to amplification, mutation, or both of the EGFR gene is common in glioblastomas. However, glioblastomas are resistant to EGFR tyrosine kinase inhibitors (EGFR-TKIs), and overcoming resistance is essential. Brexpiprazole is a new, safe serotonin-dopamine activity modulator used for schizophrenia and depression that was recently reported to have anti-CSC activity and function as a chemosensitizer. Here, we examined its chemosensitization effects on osimertinib, a third-generation EGFR-TKI with an excellent safety profile, in glioma stem cells (GSCs), which are CSCs of glioblastoma. Brexpiprazole treatment sensitized GSCs to osimertinib and reduced the expression of survivin, an antiapoptotic factor, and the pharmacological and genetic inhibition of survivin mimicked the effects of brexpiprazole. Moreover, co-treatment of brexpiprazole and osimertinib suppressed tumor growth more efficiently than either drug alone without notable toxicity in vivo. This suggests that the combination of brexpiprazole and osimertinib is a potential therapeutic strategy for glioblastoma by chemosensitizing GSCs through the downregulation of survivin expression.