Novel Poly(Adenosine Diphosphate-Ribose) Polymerase (PARP) Inhibitor, AZD2461, Down-Regulates VEGF and Induces Apoptosis in Prostate Cancer Cells

Abstract

Background: Prostate cancer (Pca) is a heterogeneous disease, and current treatments are not based on molecular stratification. Poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors have recently been found to be remarkably toxic to cells with defects in homologous recombination, particularly cells with BRCA-mutated backgrounds. Therefore, this preliminary study was designed to evaluate whether PTEN expression status could have an impact on the sensitivity of invasive Pca cells to the PARP inhibitor, AZD2461. Methods: MTT viability test, Annexin V-FITC/propidium iodide double staining, and caspase3 activity assay were used to evaluate the apoptosis and relative expression of PTEN and VEGF in PC-3 and DU145 cell lines using real-time PCR. Results: MTT results showed that the inhibitory effects of AZD2461 were higher in PC-3 than DU145 cells (with IC 50 of 36.48 and 59.03 µM at 48 hours of treatment, respectively). Flow cytometric analysis also showed the same results. When exposed to 40 µM of AZD2461, PC-3 (38.8%) and DU145 (28%) cells underwent apoptosis (p < 0.05). Treatment of cells by AZD2461 also caused a significant increase in apoptosis through caspase3 activation in both cell lines. VEGF mRNA levels in PC-3 cells significantly decreased compared to adjusted untreated cells (p < 0.05) in all measured times while displaying different alteration patterns in DU145 cells (p < 0.05). Conclusion: AZD2461 suppresses the growth of prostate tumor cells since AZD2461 monotherapy could prove to be efficacious, especially against cells not expressing PTEN besides activating the possible apoptosis-independent cell death pathways.

Adenosine interaction with adenosine receptor A2a promotes gastric cancer metastasis by enhancing PI3K–AKT–mTOR signaling

“…We also detected the tumor metastasis–related matrix metalloproteinases (MMPs) and found that adenosine increased MMP-2, MMP-7, MMP-9, and MMP-13 expression in the MKN45 cells, but that SCH 58261 blocked this effect (Figure 2D). However, the expression of MMP9, 48 h and 72 h decreased slightly more than 24 h, which may be related to adenosine-induced tumor cell apoptosis (Sargazi et al , 2019; Soleimani et al , 2019). Collectively, these findings demonstrate that adenosine promotes tumor invasion and metastasis in GC through the A2aR pathway.…”

Tumor-Suppressor Gene Transmembrane Protein 98 Promotes Proliferation and Inhibits Apoptosis in Ovarian Cancer

“…The previous study has shown that PARP activity is necessary for repairing single-strand DNA breakage [32]. Therefore, inhibition of PARP function can lead to apoptosis of homologous recombinant tumor cells [33]. PARP inhibitors are the biggest advance in the treatment of OC in recent years [34].…”

Olaparib Suppresses MDSC Recruitment via SDF1α/CXCR4 Axis to Improve the Anti-tumor Efficacy of CAR-T Cells on Breast Cancer in Mice

“…In addition, it has been reported that in tumors, PARPi had anti-angiogenesis potential through suppressing VEGFa expression. 28,43 CD31 is known as a platelet-endothelial cell adhesion molecule and is expressed on the surface of vascular endothelial cells. Our results showed that CD31 + cells were decreased in tumor tissue after the combined therapy compared with the CAR-T cell treatment alone (Figures 3J and 4J), suggesting the combined therapy has an anti-angiogenesis capacity.…”