Department of Agricultural Chemistry, National Taiwan University, 1 Sec. 4, Roosevelt Road, Taipei, 6836, 10617, Taiwan.
Department of Surgery, National Taiwan University Hospital, No.7, Chung Shan S. Rd., Zhongzheng Dist, Taipei City, 100225, Taiwan.
Cell Oncol (Dordr). 2023 Aug;46(4):1127-1142. doi: 10.1007/s13402-023-00804-x. Epub 2023 Apr 17.
Breast cancer is the most common cancer in women. Triple-negative breast cancer (TNBC) is an aggressive disease with poor outcomes. TNBC lacks effective targeted treatments, and the development of drug resistance limits the effectiveness of chemotherapy. It is crucial to identify new drugs that can enhance the efficacy of traditional chemotherapy to reduce drug resistance and side effects.
TNBC cell lines, MDA-MB-231 and Hs 578T, and a normal cell line, MCF-10 A, were included in this study. The cells were treated with gallium maltolate (GaM), and their transcriptome was analyzed. Ferroptosis and nucleolar stress markers were detected by qPCR, western blotting, fluorescence microscopy, and flow cytometry. The impairment of ribosome synthesis was evaluated by northern blotting and sucrose gradients.
GaM triggered cell death via apoptosis and ferroptosis. In addition, GaM impaired translation and activated nucleolar stress. Cisplatin (DDP) is a chemotherapeutic agent for advanced breast cancer. While single treatment with GaM or DDP at low concentrations did not impact cell growth, co-administration enhanced cell death in TNBC but not in normal breast cells. The enhancement of ferroptosis and nucleolar stress could be observed in TNBC cell lines after co-treatment.
These results suggest that GaM synergizes with cisplatin via activation of nucleolar stress and ferroptosis in human breast carcinoma cells. GaM is marginally toxic to normal cells but impairs the growth of TNBC cell lines. Thus, GaM has the potential to be used as a therapeutic agent against TNBC.
乳腺癌是女性最常见的癌症。三阴性乳腺癌（TNBC）是一种侵袭性疾病，预后不良。TNBC 缺乏有效的靶向治疗，耐药性的发展限制了化疗的效果。因此，寻找能够增强传统化疗效果的新药以减少耐药性和副作用至关重要。
本研究纳入了 TNBC 细胞系 MDA-MB-231 和 Hs 578T 以及正常细胞系 MCF-10A。用 GaM 处理这些细胞，并分析其转录组。通过 qPCR、western blot、荧光显微镜和流式细胞术检测铁死亡和核仁应激标志物。通过 northern blot 和蔗糖梯度评估核糖体合成的损伤。
GaM 通过细胞凋亡和铁死亡引发细胞死亡。此外，GaM 还损害了翻译并激活了核仁应激。顺铂（DDP）是晚期乳腺癌的化疗药物。虽然单独使用 GaM 或 DDP 低浓度不会影响细胞生长，但联合用药会增强 TNBC 细胞的细胞死亡，但对正常乳腺细胞没有影响。在联合治疗后，可观察到 TNBC 细胞系中出现铁死亡和核仁应激增强。
这些结果表明，GaM 通过激活核仁应激和铁死亡，与顺铂在人乳腺癌细胞中产生协同作用。GaM 对正常细胞仅有轻微毒性，但会损害 TNBC 细胞系的生长。因此，GaM 有可能被用作治疗 TNBC 的药物。
