S1PR2 inhibitors potently reverse 5-FU resistance by downregulating DPD expression in colorectal cancer.
S1PR2 inhibitors potently reverse 5-FU resistance by downregulating DPD expression in colorectal cancer.
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DOI：
10.1016/j.phrs.2020.104717
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发表时间：
2020-02
影响因子：
9.3
通讯作者：
Yu-Hang Zhang;D. Luo;Shengbiao Wan;Xian-Jun Qu
中科院分区：
文献类型：
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作者：
Yu-Hang Zhang;D. Luo;Shengbiao Wan;Xian-Jun Qu
在本研究中，S1PR2被认为是一个全新的GPCR靶点，用于设计逆转5-FU耐药性的抑制剂。本论文设计、合成了一系列吡咯烷类吡唑类化合物作为S1PR2抑制剂，并对其抗FU耐药活性进行了评价。其中，最有希望的化合物JTE-013在多种人癌细胞株中表现出良好的抑制DPD表达和较强的抗FU耐药活性，在活体HCT116DPD细胞移植模型中，5-FU的抑制率从13.01%-75.87%显著提高。其机制是通过阻断S1PR2内化到内质网(ER)，从而抑制5-FU降解为α-氟-β-丙氨酸(FBAL)，从而下调肿瘤DPD的表达，从而发挥抗FU耐药的作用。总之，JTE-013可以作为发现新的抗FU耐药药物的先导化合物。意义本研究为S1PR2抑制剂在结直肠癌5-FU治疗中的增敏提供了新的见解。
In this study, S1PR2 was reckoned as a brand-new GPCR target for designing inhibitors to reverse 5-FU resistance. Herein a series of pyrrolidine pyrazoles as the S1PR2 inhibitors were designed, synthesized and evaluated for their activities of anti-FU-resistance. Among them, the most promising compound JTE-013, exhibited excellent inhibition on DPD expression and potent anti-FU-resistance activity in various human cancer cell lines, along with thein vivoHCT116DPDcells xenograft model, in which the inhibition rate of 5-FU was greatly increased from 13.01%–75.87%. The underlying mechanism was uncovered that JTE-013 demonstrated an anti-FU-resistance activity by blocking S1PR2 internalization to the endoplasmic reticulum (ER), which inhibited the degradation of 5-FU into α-fluoro-β-alanine (FBAL) by downregulating tumoral DPD expression. Overall, JTE-013 could serve as the lead compound for the discovery of new anti-FU-resistance drugs.SignificanceThis study provides novel insights that S1PR2 inhibitors could sensitize 5-FU therapy in colorectal cancer.