S1PR2 inhibitors potently reverse 5-FU resistance by downregulating DPD expression in colorectal cancer. (May 2020)

• Record Type: Journal Article
• Authors: Zhang, Yu-Hang; Luo, Dong-Dong; Wan, Sheng-Biao; Qu, Xian-Jun
• Is Part Of: Pharmacological research. Volume 155(2020)
• Publication Date: 2020-05
• Subjects: Colorectal cancer (CRC) -- S1P receptor 2 (S1PR2) -- Dihydropyrimidine dehydrogenase (DPD) -- 5-FU resistance; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2020.104717
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Highlights: S1PR2 is the potential upstream regulator of DPD expression in CRC cells. JTE-013 effectively reversed 5-FU resistance of CRC both in vivo and in vitro . JTE-013 levels off DPD-catalyzed degradation of intracellular 5-FU in CRC. Abstract: 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 the in vivo HCT116 DPD cells 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. Significance: This study provides novel insights that S1PR2 inhibitors could sensitize 5-FU therapy in colorectal cancer.