Zhang Hongmei, Liu Chunling, Jin Ye, Wang Zheng, Guan Yi, Jia Zhenxian, Cui Tong, Zhang Zhi, Zhang Xuemei
Hebei Key Laboratory of Occupational Health and Safety for Coal Industry, School of Public Health, North China University of Science and Technology, Tangshan, Hebei, China.
School of Clinical Medicine, North China University of Science and Technology, Tangshan, Hebei, China.
Front Pharmacol. 2024 Oct 23;15:1494265. doi: 10.3389/fphar.2024.1494265. eCollection 2024.
Anlotinib, a highly selective inhibitor of VEGFR2, has demonstrated significant anti-tumor effects in various cancers. However, its potential synergistic effects with DDP (cisplatin) in breast cancer (BRCA) remain to be fully elucidated. This study aims to discover the therapeutic efficacy of anlotinib on BRCA, specifically the synergistic effects with DDP, and to elucidate the underlying molecular mechanisms.
BRCA cells were treated with anlotinib and/or DDP. The proliferation, migration and invasion capabilities of BRCA cells were evaluated using CCK-8 assays, cell cycle distribution, clone formation assays, wound healing assays and transwell assays. Cell apoptosis was detected by flow cytometry technique and Hoechst33342 fluorescence staining. The potential mechanism of anlotinib in the development of BRCA was predicted through bioinformatics analysis, and the mRNA or protein levels were subsequently quantified using qPCR, immunofuorescence and western blot. The anti-breast cancer efficacy of anlotinib was evaluated using a xenograft tumor model.
Our findings reveal that increased VEGFA expression in BRCA patients is associated with poorer prognosis, underscoring the need for targeted therapeutic strategies. We also demonstrate that both anlotinib and DDP independently inhibit BRCA cell growth, migration, and invasion, while their combination exhibits a synergistic effect, significantly enhancing the inhibition of these oncogenic processes. This synergy is further evident through the induction of apoptosis and autophagy in BRCA cells. Mechanistically, anlotinib's effectiveness is linked to its inhibition of the JAK2/STAT3 pathway, a critical axis in BRCA progression. study further support these results, showing that anlotinib markedly inhibits tumor growth in xenografted mice.
This study confirms the efficacy of anlotinib or in combination with DDP and elucidates the mechanism behind anlotinib's effectiveness, highlighting its role in inhibiting the JAK2/STAT3 pathway.
安罗替尼是一种高度选择性的血管内皮生长因子受体2（VEGFR2）抑制剂，已在多种癌症中显示出显著的抗肿瘤作用。然而，其与顺铂（DDP）在乳腺癌（BRCA）中的潜在协同作用仍有待充分阐明。本研究旨在探讨安罗替尼对BRCA的治疗效果，特别是与DDP的协同作用，并阐明其潜在的分子机制。
用安罗替尼和/或DDP处理BRCA细胞。使用CCK-8法、细胞周期分布、克隆形成试验、伤口愈合试验和Transwell试验评估BRCA细胞的增殖、迁移和侵袭能力。通过流式细胞术和Hoechst33342荧光染色检测细胞凋亡。通过生物信息学分析预测安罗替尼在BRCA发生发展中的潜在机制，随后使用qPCR、免疫荧光和蛋白质印迹法定量mRNA或蛋白质水平。使用异种移植肿瘤模型评估安罗替尼的抗乳腺癌疗效。
我们的研究结果表明，BRCA患者中血管内皮生长因子A（VEGFA）表达增加与较差的预后相关，这突出了靶向治疗策略的必要性。我们还证明，安罗替尼和DDP均可独立抑制BRCA细胞的生长、迁移和侵袭，而它们的联合使用则表现出协同作用，显著增强了对这些致癌过程的抑制作用。这种协同作用在诱导BRCA细胞凋亡和自噬方面更加明显。从机制上讲，安罗替尼的有效性与其对Janus激酶2/信号转导和转录激活因子3（JAK2/STAT3）通路的抑制有关，这是BRCA进展中的关键轴。体内研究进一步支持了这些结果，表明安罗替尼显著抑制异种移植小鼠的肿瘤生长。
本研究证实了安罗替尼单药或与DDP联合使用的疗效，并阐明了安罗替尼有效性背后的机制，突出了其在抑制JAK2/STAT3通路中的作用。
