Abstract：
Breast cancer is one of the most prevalent malignancies among women. Enhancing the prognosis is an effective approach to enhance the survival rate of breast cancer. Cuproptosis, a copper-dependent programmed cell death process, has been associated with patient prognosis. Inducing cuproptosis is a promising approach for therapy. However, there is currently no anti-breast cancer drug that induces cuproptosis. In this study, we repositioned the clinical drug fluphenazine as a potential agent for breast cancer treatment by inducing cuproptosis. Firstly, we utilized the Cancer Genome Atlas (TCGA) database and Connectivity Map (CMap) database to identify 22 potential compounds with anti-breast cancer activity through inducing cuproptosis. Subsequently, our findings demonstrated that fluphenazine effectively suppressed the viability of MCF-7 cells. Fluphenazine also significantly inhibited the viability of triple negative breast cancer cells MDA-MB-453 and MDA-MB-231. Furthermore, our study revealed that fluphenazine significantly down-regulated the expression of potential prognostic biomarkers associated with cuproptosis, increased copper ion levels, and reduced intracellular pyruvate accumulation. Additionally, it up-regulated the expression of FDX1 at both the mRNA and protein levels, which has been reported to play a crucial role in the induction of cuproptosis. These findings suggest that fluphenazine has the potential to be used as an anti-breast cancer drug by inducing cuproptosis. Therefore, this research provides an insight for the development of novel cuproptosis-dependent anti-cancer agents.
摘要：
乳腺癌是女性中最常见的恶性肿瘤之一。提高预后是提高乳腺癌生存率的有效途径。角化,铜依赖的程序性细胞死亡过程，与患者预后相关。诱导角化是一种有前途的治疗方法。然而,目前还没有抗乳腺癌药物能诱导角化。在这项研究中,我们通过诱导细胞凋亡将临床药物氟奋乃静重新定位为乳腺癌治疗的潜在药物.首先,我们利用癌症基因组图谱(TCGA)数据库和连接图(CMap)数据库鉴定了22种通过诱导角化而具有抗乳腺癌活性的潜在化合物.随后，我们的研究结果表明，氟奋乃静有效抑制MCF-7细胞的活力。氟奋乃静还显著抑制三阴性乳腺癌细胞MDA-MB-453和MDA-MB-231的活力。此外，我们的研究表明，氟奋乃静显著下调潜在的预后相关的生物标志物的表达，增加铜离子水平，减少细胞内丙酮酸积累。此外,它在mRNA和蛋白质水平上上调FDX1的表达，据报道，这在诱导角化凋亡中起着至关重要的作用。这些发现表明，氟奋乃静具有通过诱导角化而被用作抗乳腺癌药物的潜力。因此,这项研究为新型依赖角化的抗癌药的开发提供了见解。
