Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China; Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China.
Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China; Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China.
Toxicol Appl Pharmacol. 2023 Sep 15;475:116647. doi: 10.1016/j.taap.2023.116647. Epub 2023 Aug 4.
As highly expressed in several human cancers, Casein Kinase 2 (CK2) is involved in chemotherapy-induced resistance. As a new potent CK2 inhibitor, DN701 is used to overcome chemoresistance through its synergistic antitumor effect with 5-fluorouracil (5-FU). Translesion DNA synthesis (TLS) has drawn our attention because it is associated with the development of chemo-resistance and tumor recurrence. The in vitro biological properties of 5-FU-resistant colon cancer cells revealed that DN701 combined with 5-FU could overcome chemo-resistance via blocking CK2-mediated aryl hydrocarbon receptor (AhR) and TLS-induced DNA damage repair (DDR). Moreover, pharmacologic and genetic inhibitions of AhR potently reduced TLS-promoted genomic instability. The mechanistic studies showed that combined DN701 with 5-FU was investigated to inhibit CK2 expression level and AhR-TLS-REV1 pathway. Meanwhile, DN701 combined with 5-FU could reduce CK2-AhR-TLS genomic instability, thus leading to superior in vivo antitumor effect. The insights provide a rationale for combining DN701 with 5-FU as a therapeutic strategy for patients with colon cancer.
在几种人类癌症中高度表达的酪蛋白激酶 2（CK2）参与了化疗诱导的耐药性。DN701 是一种新型有效的 CK2 抑制剂，通过与 5-氟尿嘧啶（5-FU）的协同抗肿瘤作用来克服耐药性。跨损伤 DNA 合成（TLS）引起了我们的注意，因为它与化疗耐药性的发展和肿瘤复发有关。5-FU 耐药性结肠癌细胞的体外生物学特性表明，DN701 联合 5-FU 通过阻断 CK2 介导的芳香烃受体（AhR）和 TLS 诱导的 DNA 损伤修复（DDR）来克服耐药性。此外，AhR 的药理学和遗传学抑制有力地降低了 TLS 促进的基因组不稳定性。机制研究表明，联合使用 DN701 和 5-FU 可抑制 CK2 的表达水平和 AhR-TLS-REV1 通路。同时，DN701 联合 5-FU 可减少 CK2-AhR-TLS 基因组不稳定性，从而导致体内抗肿瘤效果更好。这些研究结果为将 DN701 与 5-FU 联合作为结肠癌患者的治疗策略提供了依据。
