Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan Province, 450001, PR China.
Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, Henan Province, 450001, PR China.
Oncogene. 2023 Jul;42(29):2278-2293. doi: 10.1038/s41388-023-02750-2. Epub 2023 Jun 22.
Cisplatin (CDDP) is the first-line drug in the clinical treatment of esophageal squamous cell carcinoma (ESCC), which has severe nephrotoxicity. Diosmetin (DIOS) can protect kidney from oxidative damage, however, its function in ESCC is unknown. This study aims to explore the effect and mechanism of DIOS on ESCC and its combined effect with CDDP. Herein, we found that DIOS significantly inhibited the progression of ESCC in vitro and in vivo. Furthermore, the anti-tumor effect of DIOS was not statistically different from that of CDDP. Mechanically, transcriptomics revealed that DIOS inhibited the E2F2/RRM2 signaling pathway. The transcriptional regulation of RRM2 by E2F2 was verified by luciferase assay. Moreover, docking model, CETSA, pull-down assay and CDK2 inhibitor assay confirmed that DIOS directly targeted CDK2, leading to significant suppression of ESCC. Additionally, the patient-derived xenografts (PDX) model showed that the combination of DIOS and CDDP significantly inhibited the growth of ESCC. Importantly, the combined treatment with DIOS and CDDP significantly reduced the mRNA expression levels of kidney injury biomarkers KIM-1 and NGAL in renal tissue, as well as the levels of blood urea nitrogen, serum creatinine and blood uric acid compared to the single treatment with CDDP. In conclusion, DIOS could be an effective drug and a potential chemotherapeutic adjuvant for ESCC treatment. Furthermore, DIOS could reduce the nephrotoxicity of CDDP to some extent.
顺铂（CDDP）是食管鳞癌（ESCC）临床治疗的一线药物，具有严重的肾毒性。香叶木素（DIOS）可以保护肾脏免受氧化损伤，但它在 ESCC 中的作用尚不清楚。本研究旨在探讨 DIOS 对 ESCC 的作用及其与 CDDP 的联合作用。在此，我们发现 DIOS 可显著抑制 ESCC 的体外和体内进展。此外，DIOS 的抗肿瘤作用与 CDDP 无统计学差异。从机制上看，转录组学显示 DIOS 抑制了 E2F2/RRM2 信号通路。通过荧光素酶测定验证了 E2F2 对 RRM2 的转录调控。此外，对接模型、CETSA、下拉实验和 CDK2 抑制剂实验证实 DIOS 可直接靶向 CDK2，从而显著抑制 ESCC。此外，患者来源的异种移植（PDX）模型表明，DIOS 与 CDDP 的联合治疗可显著抑制 ESCC 的生长。重要的是，与单独使用 CDDP 相比，联合使用 DIOS 和 CDDP 可显著降低肾组织中肾损伤标志物 KIM-1 和 NGAL 的 mRNA 表达水平，以及血尿素氮、血清肌酐和血尿酸水平。总之，DIOS 可能是一种有效的药物，也是 ESCC 治疗的一种有潜力的化疗辅助药物。此外，DIOS 可在一定程度上降低 CDDP 的肾毒性。
