School of Life Science and Technology, School of Engineering, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, People's Republic of China.
Department of Pharmacy, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, 127 Dongming Road, Zhengzhou, 450003, People's Republic of China.
Cell Mol Life Sci. 2022 Jun 11;79(7):360. doi: 10.1007/s00018-022-04384-1.
Breast cancer stem cells (BCSCs) are positively correlated with the metastasis, chemoresistance, and recurrence of breast cancer. However, there are still no drugs targeting BCSCs in clinical using for breast cancer treatment. Here, we tried to screen out small-molecule compounds targeting BCSCs from the phenazine library established by us before. We focused on the compounds without affecting cell viability and screened out three potential compounds (CPUL119, CPUL129, CPUL149) that can significantly attenuate the stemness of breast cancer cells, as evident by the decrease of stemness marker expression, CD44/CD24 subpopulation, mammary spheroid-formation ability, and tumor-initiating capacity. Additionally, these compounds suppressed the metastatic ability of breast cancer cells in vitro and in vivo. Combined with the transcriptome sequencing analysis, ferroptosis was shown on the top of the most upregulated pathways by CPUL119, CPUL129, and CPUL149, respectively. Mechanistically, we found that these three compounds could trigger ferroptosis by accumulating and sequestering iron in lysosomes through interacting with iron, and by regulating the expression of proteins (IRP2, TfR1, ferritin) engaged in iron transport and storage. Furthermore, inhibition of ferroptosis rescued the suppression of these three compounds on breast cancer cell stemness. This study suggests that CPUL119, CPUL129, and CPUL149 can specifically inhibit the stemness of breast cancer cells through triggering ferroptosis and may be the potential compounds for breast cancer treatment.
乳腺癌干细胞（BCSCs）与乳腺癌的转移、化疗耐药和复发呈正相关。然而，目前临床上仍没有针对 BCSCs 的药物用于乳腺癌的治疗。在这里，我们试图从前人建立的吩嗪文库中筛选出针对 BCSCs 的小分子化合物。我们重点关注对细胞活力没有影响的化合物，并筛选出三种可能的化合物（CPUL119、CPUL129 和 CPUL149），它们可以显著削弱乳腺癌细胞的干性，表现为干性标志物表达、CD44/CD24 亚群、乳腺球体形成能力和肿瘤起始能力降低。此外，这些化合物在体外和体内均抑制了乳腺癌细胞的转移能力。结合转录组测序分析，CPUL119、CPUL129 和 CPUL149 分别使铁死亡相关途径在最上调途径中排名靠前。从机制上讲，我们发现这三种化合物可以通过与铁相互作用在溶酶体中积累和隔离铁，并通过调节铁转运和储存相关蛋白（IRP2、TfR1、铁蛋白）的表达来触发铁死亡。此外，抑制铁死亡可以挽救这三种化合物对乳腺癌细胞干性的抑制作用。本研究表明，CPUL119、CPUL129 和 CPUL149 可以通过诱导铁死亡特异性抑制乳腺癌细胞的干性，可能是治疗乳腺癌的潜在化合物。
