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Identification of amentoflavone as a potent highly selective PARP-1 inhibitor and its potentiation on carboplatin in human non-small cell lung cancer
- Source :
- Phytomedicine : international journal of phytotherapy and phytopharmacology. 50
- Publication Year :
- 2018
-
Abstract
- Background Nuclear protein poly (ADP-ribose) polymerase-1 (PARP-1) is a key enzyme in the repair of DNA and is a promising target in the development of chemosensitizers. This study first investigated the inhibitory effects of amentoflavone (AMF) and its derivatives on PARP-1 and the potentiation of AMF on carboplatin (CBP) in non-small cell lung cancer (NSCLC). Purpose This study aims to evaluate the inhibitory effect of AMF against PARP-1 and its potentiation on CBP in lung cancer both in vitro and in vivo. Study design The inhibitory effect of AMF on PARP-1 was investigated using molecular docking and cell-free model of PARP-1 assay. Its potentiation on CBP in lung cancer was also evaluated. Methods Fluorescence resonance energy transfer assay was used to detect the inhibitory effects of AMF and its analogues on PARP-1. Molecular docking was employed to predict the binding mode of AMF and PARP-1. MTT assay, isobologram analysis, Hoechst staining, and Annexin V-PI double staining were used to confirm the potentiation of AMF on CBP in vitro. siRNA (PARP-1)-A549 cells were used to reveal the action target of AMF. Western blot analysis, immunohistochemistry, and Tunnel assay were employed to evaluate the potentiation of AMF on CBP in A549 xenograft mice. Results AMF and its analogues exerted excellent inhibitory effects on PARP-1 with IC50 values ranging from 0.198 μM to 0.409 μM. Docking experiment showed that AMF can stably bind to PARP-1 with a comparable binding energy to olaparib. AMF can decrease the expression of PAR induced by H2O2 in vitro. AMF synergistically increased the CBP anti-proliferative effect in A549. However, its potentiation nearly disappeared when the cells were transfected with siRNAs against PARP-1. Oral administration of AMF (100 mg/kg), combined with CBP, remarkably inhibited A549 tumor growth and ki67 expression, and increased apoptosis compared with CBP-alone group. Conclusion All results suggest that AMF can be a potential PARP-1 inhibitor and a candidate adjuvant agent to boost the anticancer effect of CBP in NSCLC.
- Subjects :
- 0301 basic medicine
Lung Neoplasms
Chemosensitizer
Poly (ADP-Ribose) Polymerase-1
Pharmaceutical Science
Mice, Nude
Apoptosis
Amentoflavone
Piperazines
Olaparib
Carboplatin
03 medical and health sciences
chemistry.chemical_compound
Mice
0302 clinical medicine
Western blot
In vivo
Carcinoma, Non-Small-Cell Lung
Drug Discovery
medicine
Animals
Biflavonoids
Humans
MTT assay
Pharmacology
A549 cell
medicine.diagnostic_test
Molecular Structure
Chemistry
fungi
Xenograft Model Antitumor Assays
In vitro
Molecular Docking Simulation
030104 developmental biology
Complementary and alternative medicine
A549 Cells
030220 oncology & carcinogenesis
Cancer research
Molecular Medicine
Phthalazines
Female
Subjects
Details
- ISSN :
- 1618095X
- Volume :
- 50
- Database :
- OpenAIRE
- Journal :
- Phytomedicine : international journal of phytotherapy and phytopharmacology
- Accession number :
- edsair.doi.dedup.....dd81861bfcd47d705deaaec21d9c4a21