Huang Lili, Wei Yingying, Ni Maowei, Hu Hongtao, Xi Luyi, Wang Chen, Zhu Zhihui, Yang Bo, Zhao Huajun
School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Gaoke Rd., Hangzhou 311402, China.
The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou 310022, China.
Molecules. 2024 Apr 18;29(8):1838. doi: 10.3390/molecules29081838.
Triple-negative breast cancer (TNBC) is a malignant breast cancer. There is an urgent need for effective drugs to be developed for TNBC. () has been reported to have an anti-tumor effect, and six novel withanolides were isolated from it and designated as TAMEWs. However, its anti-TNBC effect is still unknown. The results of an MTT assay indicated a higher sensitivity of TNBC cells to TAMEWs compared to other cells. TAMEWs induced apoptosis via mitochondrial dysfunction. They caused increased levels of lipid ROS and Fe, with downregulation of GSH and cystine uptake, and it has been confirmed that TAMEWs induced ferroptosis. Additionally, the results of Western blotting indicate that TAMEWs significantly decrease the expressions of ferroptosis-related proteins. Through further investigation, it was found that the knockdown of the p53 gene resulted in a significant reversal of ferroptosis and the expressions of its associated proteins SLC7A11, ASCT2, and GPX4. In vivo, TAMEWs suppressed TNBC growth with no obvious damage. The IHC results also showed that TAMEWs induced apoptosis and ferroptosis in vivo. Our findings provide the first evidence that TAMEWs suppress TNBC growth through apoptosis and ferroptosis.
三阴性乳腺癌（TNBC）是一种恶性乳腺癌。迫切需要开发针对TNBC的有效药物。（）已被报道具有抗肿瘤作用，并且从中分离出六种新型的睡茄内酯并将其命名为TAMEWs。然而，其抗TNBC作用仍然未知。MTT分析结果表明，与其他细胞相比，TNBC细胞对TAMEWs更敏感。TAMEWs通过线粒体功能障碍诱导细胞凋亡。它们导致脂质ROS和铁水平升高，同时谷胱甘肽和胱氨酸摄取下调，并且已经证实TAMEWs诱导铁死亡。此外，蛋白质印迹结果表明TAMEWs显著降低铁死亡相关蛋白的表达。通过进一步研究发现，p53基因的敲低导致铁死亡及其相关蛋白SLC7A11、ASCT2和GPX4的表达显著逆转。在体内，TAMEWs抑制TNBC生长且无明显损伤。免疫组化结果还表明TAMEWs在体内诱导细胞凋亡和铁死亡。我们的研究结果首次证明TAMEWs通过细胞凋亡和铁死亡抑制TNBC生长。
