ABSTRACT
Inducing the deficiency of homologous recombination (HR) repair is an effective strategy to broaden the indication of PARP inhibitors in pancreatic cancer treatment. Repression of BRD4 has been reported to significantly elevate HR deficiency and sensitize cancer cells to PARP1/2 inhibitors. Inspired by the concept of synthetic lethality, we designed, synthetized and optimized a dual PARP1/BRD4 inhibitor III-7, with a completely new structure and high selectivity against both targets. III-7 repressed the expression and activity of PARP1 and BRD4 to synergistically inhibit the malignant growth of pancreatic cancer cells in vitro and in vivo. Based on the results of bioinformatic analysis, we found that Olaparib induced the acceleration of mitosis and recovery of DNA repair to cause the generation of drug resistance. III-7 reversed Olaparib-induced adaptive resistance and induced cell cycle arrest and DNA damage by perturbing PARP1 and BRD4-involved signaling pathways. We believe that the PARP1/BRD4 dual inhibitors are novel and promising antitumor agents, which provide an efficient strategy for pancreatic cancer treatment.
Subject(s)
Cell Cycle Proteins/antagonists & inhibitors , Pancreatic Neoplasms , Transcription Factors/antagonists & inhibitors , Cell Line, Tumor , Humans , Pancreatic Neoplasms/drug therapy , Phthalazines/pharmacology , Poly (ADP-Ribose) Polymerase-1/antagonists & inhibitors , Poly(ADP-ribose) Polymerase Inhibitors/pharmacologyABSTRACT
Targeting poly(ADP-ribose) polymerase1/2 (PARP1/2) is a promising strategy for the treatment of pancreatic cancer with breast cancer susceptibility gene (BRCA) mutation. Inducing the deficiency of homologous recombination (HR) repair is an effective way to broaden the indication of PARP1/2 inhibitor for more patients with pancreatic cancer. Bromodomain-containing protein 4 (BRD4) repression has been reported to elevate HR deficiency. Therefore, we designed, synthetized, and optimized a dual PARP/BRD4 inhibitor III-16, with a completely new structure and high selectivity against PARP1/2 and BRD4. III-16 showed favorable synergistic antitumor efficacy in pancreatic cancer cells and xenografts by arresting cell cycle progression, inhibiting DNA damage repair, and promoting autophagy-associated cell death. Moreover, III-16 reversed Olaparib-induced acceleration of cell cycle progression and recovery of DNA repair. The advantages of III-16 over Olaparib suggest that dual PARP/BRD4 inhibitors are novel and promising agents for the treatment of advanced pancreatic cancer.
Subject(s)
Antineoplastic Agents/therapeutic use , Cell Cycle Proteins/antagonists & inhibitors , Drug Discovery , Pancreatic Neoplasms/drug therapy , Phthalazines/therapeutic use , Piperazines/therapeutic use , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Transcription Factors/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Autophagy/drug effects , DNA Damage , DNA Repair , Gene Expression Regulation, Neoplastic/drug effects , Genes, BRCA1 , Humans , Pancreatic Neoplasms/pathology , Phthalazines/pharmacology , Piperazines/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Rad51 Recombinase/geneticsABSTRACT
MicroRNA-873 (miR873) has been reported to be dysregulated in a variety of malignancies, however, the biological function and underlying molecular mechanism of miR873 in colorectal cancer (CRC) remain unclear. In the present study we found that the expression levels of miR873 were markedly decreased in CRC cell lines and tissues from patients. Statistical analysis revealed that miR873 expression was inversely correlated with the disease stage of CRC. KaplanMeier survival analysis revealed that patients with CRC with lower miR873 expression had shorter overall survival rates. Additionally, downregulation of miR873 enhanced the proliferation of CRC cells, while upregulation of miR873 reduced this proliferation. Furthermore, we found that tumor necrosis factor (TNF) receptor-associated factor 5 (TRAF5) and TGFß activated kinase 1 (MAP3K7) binding protein 1 (TAB1) were direct targets of miR873 in CRC cells. A luciferase assay revealed that ectopic expression of miR873 significantly reduced nuclear factor κB (NFκB) luciferase activity, while ectopic expression of miR873 inhibitor enhanced luciferase activity, suggesting that downregulation of miR873 can activate NFκB signaling. Therefore, our findings established a tumor-suppressive role for miR873 in the inhibition of CRC progression, which may be employed as a novel prognostic marker and as an effective therapeutic target for CRC.