Li Yi, Dong Yuyan
Department of Gynaecology, Shandong Provincial Third Hospital, Shandong University, No.11 Wuyingshan Middle Road, Tianqiao District, Jinan, 250031, Shandong, People's Republic of China.
Department of Gynaecology, Shandong Provincial Maternal and Child Health Care Hospital, 238 Jingshi East Road, Jinan, 250014, Shandong, People's Republic of China.
Cancer Cell Int. 2024 Aug 12;24(1):286. doi: 10.1186/s12935-024-03463-6.
Cervical cancer (CC) is a significant global health concern, demanding the consideration of novel therapeutic strategies. The signal transducer and activator of transcription 3 (STAT3) pathway has been implicated in cancer progression and is a potential target for therapeutic intervention. This study aimed to explore the therapeutic potential of TTI-101, a small molecule STAT3 inhibitor, in CC and investigate its underlying mechanisms.
Molecular docking studies and molecular dynamics simulations were performed to explore the binding interaction between TTI-101 and STAT3 and assess the stability of the STAT3-TTI-101 complex. Cell viability assays, wound healing assays, colony formation assays, flow cytometry analysis, and gene expression analysis were conducted. In vivo xenograft models were used to assess the antitumor efficacy of TTI-101.
The in silico analysis shows a stable binding interaction between TTI-101 and STAT3. TTI-101 treatment inhibits cell viability, clonogenic ability, and cell migration in CC cells. Furthermore, TTI-101 induces apoptosis and cell cycle arrest. Analysis of apoptosis-related markers demonstrated dysregulation of Bax, Bcl-2, and Caspase-3 upon TTI-101 treatment. Moreover, TTI-101 caused G2/M phase arrest accompanied by a decrease in CDK1 and Cyclin B1 at mRNA levels. In the xenograft model, TTI-101 significantly inhibited tumor growth without adverse effects on body weight.
TTI-101 exhibited anticancer effects by targeting the STAT3/c-Myc signaling pathway, inducing cell cycle arrest, and promoting apoptosis in CC cells. These findings provide valuable insights into the development of novel therapeutic strategies for cervical cancer. Further investigation is warranted to validate the clinical application of TTI-101.
宫颈癌（CC）是一个重大的全球健康问题，需要考虑新的治疗策略。信号转导和转录激活因子3（STAT3）通路与癌症进展有关，是治疗干预的潜在靶点。本研究旨在探讨小分子STAT3抑制剂TTI-101在宫颈癌中的治疗潜力，并研究其潜在机制。
进行分子对接研究和分子动力学模拟，以探索TTI-101与STAT3之间的结合相互作用，并评估STAT3-TTI-101复合物的稳定性。进行细胞活力测定、伤口愈合测定、集落形成测定、流式细胞术分析和基因表达分析。使用体内异种移植模型评估TTI-101的抗肿瘤疗效。
计算机分析显示TTI-101与STAT3之间存在稳定的结合相互作用。TTI-101处理可抑制宫颈癌细胞的细胞活力、克隆形成能力和细胞迁移。此外，TTI-101诱导细胞凋亡和细胞周期停滞。对凋亡相关标志物的分析表明，TTI-101处理后Bax、Bcl-2和Caspase-3失调。此外，TTI-101导致G2/M期停滞，同时mRNA水平上的CDK1和细胞周期蛋白B1减少。在异种移植模型中，TTI-101显著抑制肿瘤生长，且对体重无不良影响。
TTI-101通过靶向STAT3/c-Myc信号通路、诱导细胞周期停滞和促进宫颈癌细胞凋亡发挥抗癌作用。这些发现为宫颈癌新治疗策略的开发提供了有价值的见解。有必要进一步研究以验证TTI-101的临床应用。
