Aripiprazole as an Inhibitor of the EGFR/PI3K/AKT Signaling Pathway and Sensitizer of MPA Suppressed Progestin-Resistant Endometrial Cancer Cells

IF 4.3 3区 医学 Q2 CHEMISTRY, MEDICINAL
Wen Gan, Xinyu Liu, Yikang Zhou, Wei Gu, Xiaohu Liu, Lingyi Song, Jian Li, Yudong Wang, Fei Mao
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引用次数: 0

Abstract

Drug repurposing, which involves applying existing pharmaceuticals to new therapeutic areas, offers several advantages, including increased efficiency, reduced costs, and lower risks. The research aimed to investigate the molecular mechanisms underlying the new application of the antipsychotic drug aripiprazole (APZ) in the treatment of endometrial cancer (EC), as well as its synergistic efficacy when used in combination with progestin. The cell viability assay and proliferation assay demonstrated that APZ exerted a significant inhibitory effect on the proliferation of ISK and KLE cells. Moreover, APZ was found to induce cell apoptosis prominently by flow cytometry. Network pharmacology analysis indicated that the anti-EC effects of APZ were mediated via the epidermal growth factor receptor (EGFR)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway, which was subsequently confirmed by Western blot analysis. Furthermore, APZ significantly enhanced the proliferation inhibitory effect of medroxyprogesterone acetate (MPA) against progestin-resistant KLE cells, displaying remarkable synergistic activity. These findings position APZ as a promising therapeutic candidate for EC, with potential utility both as a monotherapy and in combination with MPA, offering new avenues for EC treatment strategies.

阿立哌唑作为EGFR/PI3K/AKT信号通路抑制剂和MPA抑制孕激素抵抗子宫内膜癌细胞的增敏剂
药物再利用包括将现有药物应用于新的治疗领域,它有几个优点,包括提高效率、降低成本和降低风险。本研究旨在探讨抗精神病药物阿立哌唑(APZ)在子宫内膜癌(EC)治疗中的新应用及其与黄体酮联用的协同作用机制。细胞活力和增殖实验表明,APZ对ISK和KLE细胞的增殖有明显的抑制作用。流式细胞术发现APZ对细胞凋亡有显著的诱导作用。网络药理学分析表明,APZ的抗ec作用是通过表皮生长因子受体(EGFR)/磷脂酰肌醇3-激酶(PI3K)/蛋白激酶B (AKT)信号通路介导的,Western blot分析证实了这一点。此外,APZ显著增强醋酸甲羟孕酮(MPA)对抗孕酮KLE细胞的增殖抑制作用,表现出显著的协同作用。这些发现表明APZ是一种很有前途的治疗EC的候选药物,无论是作为单一疗法还是与MPA联合治疗,都具有潜在的效用,为EC的治疗策略提供了新的途径。
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来源期刊
Archiv der Pharmazie
Archiv der Pharmazie 医学-化学综合
CiteScore
7.90
自引率
5.90%
发文量
176
审稿时长
3.0 months
期刊介绍: Archiv der Pharmazie - Chemistry in Life Sciences is an international journal devoted to research and development in all fields of pharmaceutical and medicinal chemistry. Emphasis is put on papers combining synthetic organic chemistry, structural biology, molecular modelling, bioorganic chemistry, natural products chemistry, biochemistry or analytical methods with pharmaceutical or medicinal aspects such as biological activity. The focus of this journal is put on original research papers, but other scientifically valuable contributions (e.g. reviews, minireviews, highlights, symposia contributions, discussions, and essays) are also welcome.
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