FDI-6 and olaparib synergistically inhibit the growth of pancreatic cancer by repressing BUB1, BRCA1 and CDC25A signaling pathways. (January 2022)

• Record Type: Journal Article
• Authors: Wu, Shi-Qi; Huang, Shi-Hui; Lin, Qian-Wen; Tang, Yi-Xuan; Huang, Lei; Xu, Yun-Gen; Wang, Shu-Ping
• Is Part Of: Pharmacological research. Volume 175(2022)
• Publication Date: 2022-01
• Subjects: FDI-6 (PubChem CID: 5175738) -- Olaparib (PubChem CID: 23725625) -- Propidium bromide (PubChem CID: 16043037); PARP Poly (ADP-ribose) polymerase -- BRCA1 breast cancer susceptibility gene 1 -- BRCA2 breast cancer susceptibility gene 2 -- SSBs single-strand breaks -- DSBs double-strand breaks -- HR homologous recombination -- FOXM1 forkhead box protein M1 -- CCNB1 cyclin B1 -- CDC25A cell division cycle 25A -- CDC25B cell division cycle 25B -- BUB1 budding uninhibited by benzimidazoles -- FBS fetal bovine serum -- CI combination index -- TCGA cancer Genome Atlas -- GEPIA2 Gene Expression Profiling Interactive Analysis version 2 -- PI propidium iodide -- BSA bovine serum albumin -- H&E hematoxylin and eosin -- PAAD pancreatic adenocarcinoma -- DFS disease-free survival -- OS overall survival -- GO gene ontology -- CCND1 cyclin D1 -- CCNA2 cyclin A2 -- CDK1 cyclin-dependent kinase 1 -- XRCC2 x-ray repair cross complementing 2 -- E2F2 E2F transcription factor 2; Pancreatic cancer -- PARP1 -- FOXM1 -- Cell cycle -- DNA repair; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2021.106040
• Languages: English
• ISSNs: 1043-6618

Abstract

Abstract: Inducing homologous recombination (HR) deficiency is a promising strategy to broaden the indication of PARP1/2 inhibitors in pancreatic cancer treatment. In addition to inhibition kinases, repression of the transcriptional function of FOXM1 has been reported to inhibit HR-mediated DNA repair. We found that FOXM1 inhibitor FDI-6 and PARP1/2 inhibitor Olaparib synergistically inhibited the malignant growth of pancreatic cancer cells in vitro and in vivo . The results of bioinformatic analysis and mechanistic study showed that FOXM1 directly interacted with PARP1. Olaparib induced the feedback overexpression of PARP1/2, FOXM1, CDC25A, CCND1, CDK1, CCNA2, CCNB1, CDC25B, BRCA1/2 and Rad51 to promote the acceleration of cell mitosis and recovery of DNA repair, which caused the generation of adaptive resistance. FDI-6 reversed Olaparib-induced adaptive resistance and inhibited cell cycle progression and DNA damage repair by repressing the expression of FOXM1, PARP1/2, BUB1, CDC25A, BRCA1 and other genes-involved in cell cycle control and DNA damage repair. We believe that targeting FOXM1 and PARP1/2 is a promising combination therapy for pancreatic cancer without HR deficiency. Graphical Abstract: ga1 Highlights: FID-6 and Olaparib synergistically inhibit the expression of FOXM1 and PARP1/2. FOXM1 directly interacts with PARP1. Olaparib induces the acceleration of cell mitosis and recovery of DNA repair. FID-6 reverses Olaparib-induced adaptive resistance. BUB1, CDC25A and BRCA1 are the key genes regulated by FOXM1 and PARP1.