Title:Novel PARP Inhibitor DDPF-20 Induces DNA Damage and Inhibits Angiogenesis
through the PI3K/Akt/VEGF Pathway
Volume: 22
Issue: 13
Author(s): Tian Wang, Dong Zhang, Chuanlong Guo and Wenyong Zhu*
Affiliation:
- Department of Thoracic Surgery, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, Shandong,
266035, China
Keywords:
PARP inhibitor, A549 cells, DNA damage, angiogenesis, PI3K/Akt/VEGF, novel compound.
Abstract:
Background: Poly (ADP-ribose) polymerase (PARP) plays a key role in DNA damage repair. A novel
compound (E)-N'-(2,3-dibromo-4,5-dihydroxyphenyl)-N-(phenylcarbamothioyl)formimidamide (DDPF-20) with excellent
PARP inhibitory activity was synthesized.
Objective: In this study, we aimed to clarify the mechanism of the novel PARP inhibitor DDPF-20 against lung cancer
by inducing DNA damage and inhibiting angiogenesis.
Methods: The cytotoxic effect of DDPF-20 on the A549 cell line was determined with an MTT assay. Cell cycle and
apoptosis were determined by a flow cytometer. Moreover, the γH2AX foci were detected by immunofluorescence.
Capillary-like tube formation assay and chick chorioallantoic membrane (CAM) assay were used to detect the angiogenesis
inhibitory effect of DDPF-20. The expressions of related proteins were detected by western blot. The anticancer
activity of DDPF-20 in vivo was also detected.
Results: With an IC50 value of 52.42 ± 15.13 nM, DDPF-20 inhibited the proliferation, induced G2/M cycle arrest, and
induced apoptosis of human lung cancer A549 cells. Further research showed that DDPF-20 induced DNA doublestrand
breaks (DSBs). Interestingly, DDPF-20 inhibited the tube formation of HUVEC cells, as well as inhibited the
neovascularization of CAM, proving the angiogenesis inhibitory ability of DDPF-20. Mechanism studies proved that
DDPF-20 inhibited the PI3K/Akt/VEGF signaling pathway. In an in vivo study, DDPF-20 inhibited tumor growth of an
A549 xenograft. Analysis of the molecular mechanism underlying this effect revealed that the PI3K/Akt/VEGF pathway
was involved in DDPF-20-induced cell death and inhibited angiogenesis in vivo.
Conclusion: This study suggested that the novel PARP inhibitor DDPF-20 may have therapeutic potential in treating
lung cancer.