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FDI-6 and olaparib synergistically inhibit the growth of pancreatic cancer by repressing BUB1, BRCA1 and CDC25A signaling pathways
- Source :
- Pharmacological research. 175
- Publication Year :
- 2021
-
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.
- Subjects :
- Pharmacology
Mice, Inbred BALB C
BRCA1 Protein
Pyridines
Forkhead Box Protein M1
Mice, Nude
Apoptosis
Cell Cycle Checkpoints
Thiophenes
Poly(ADP-ribose) Polymerase Inhibitors
Protein Serine-Threonine Kinases
Piperazines
Gene Expression Regulation, Neoplastic
Pancreatic Neoplasms
Cell Line, Tumor
Animals
Humans
Phthalazines
cdc25 Phosphatases
Female
Comet Assay
Cell Proliferation
Signal Transduction
Subjects
Details
- ISSN :
- 10961186
- Volume :
- 175
- Database :
- OpenAIRE
- Journal :
- Pharmacological research
- Accession number :
- edsair.doi.dedup.....0a89479801f3d921a004fb8664bcdd19