Yuan Limei, Zhu Yaqing, Guan Gege, Liu Mei
Department of Oncology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Dongjing New District, Lumen Road 5, Xiangyang, 441100, People's Republic of China.
Department of Thyroid and Breast Surgery, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, 441100, People's Republic of China.
Cancer Chemother Pharmacol. 2025 Apr 2;95(1):51. doi: 10.1007/s00280-025-04770-z.
Chemoresistance in triple negative breast cancer (TNBC) poses a significant challenge in effective treatment, necessitating the exploration of novel therapeutic strategies. This study evaluates the efficacy of napabucasin, a potent STAT3 inhibitor, in two paclitaxel-resistant TNBC cell models (MD-MBA-231-r and BT-549-r). We observed that napabucasin significantly reduced cell viability and colony formation in a dose-dependent manner. Combination index analysis revealed synergistic interactions between napabucasin and paclitaxel, suggesting enhanced cytotoxic effects when used in combination. Mechanistically, napabucasin inhibited STAT3 signaling and impaired mitochondrial function, as evidenced by decreased phosphorylated STAT3 levels, reduced mitochondrial complex I activity, lower oxygen consumption rate and diminished ATP levels. Further analysis indicated that paclitaxel-resistant cells exhibit higher mitochondrial biogenesis and function compared to their sensitive counterparts, with elevated expression of mitochondrial genes and biogenesis regulators, and increased levels of mitochondrial respiration. In vivo, napabucasin significantly inhibited tumor growth in paclitaxel-resistant TNBC xenograft models and reduced the expression of proliferation marker Ki67 and phosphorylation of STAT3. These findings demonstrate that napabucasin effectively targets paclitaxel-resistant TNBC cells by impairing mitochondrial function and inhibiting key signaling pathways, providing a strong rationale for its further clinical investigation as a therapeutic agent to overcome chemoresistance in TBNC.
三阴性乳腺癌（TNBC）中的化学抗性对有效治疗构成了重大挑战，因此有必要探索新的治疗策略。本研究评估了强效STAT3抑制剂萘布西辛在两种耐紫杉醇TNBC细胞模型（MD-MBA-231-r和BT-549-r）中的疗效。我们观察到，萘布西辛以剂量依赖的方式显著降低细胞活力和集落形成。联合指数分析显示萘布西辛与紫杉醇之间存在协同相互作用，表明联合使用时细胞毒性作用增强。从机制上讲，萘布西辛抑制STAT3信号传导并损害线粒体功能，这可通过磷酸化STAT3水平降低、线粒体复合体I活性降低、氧消耗率降低和ATP水平降低来证明。进一步分析表明，与敏感细胞相比，耐紫杉醇细胞表现出更高的线粒体生物发生和功能，线粒体基因和生物发生调节因子的表达升高，线粒体呼吸水平增加。在体内，萘布西辛显著抑制耐紫杉醇TNBC异种移植模型中的肿瘤生长，并降低增殖标志物Ki67的表达和STAT3的磷酸化。这些发现表明，萘布西辛通过损害线粒体功能和抑制关键信号通路有效地靶向耐紫杉醇TNBC细胞，为其作为克服TBNC化学抗性的治疗剂进行进一步临床研究提供了有力依据。
