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2-Methoxy-6-Acetyl-7-Methyljuglone (MAM) Induces iNOS/NO-mediated DNA Damage Response through Activation of MAPKs Pathways
- Source :
- Anti-cancer agents in medicinal chemistry. 18(6)
- Publication Year :
- 2017
-
Abstract
- Background:There are inconsistent reports about the role of Nitric Oxide (NO) in cancer progression and prevention. Quinones demonstrate significant anti-cancer activities both in vitro and in vivo. Objective: We investigated the effect of 2-methoxy-6-acetyl-7-methyljuglone (MAM), a natural naphthoquinone isolated from Polygonum cuspidatum Sieb. et Zucc, on NO generation and its role in DNA damage in cancer cells. Methods: BEL-7402 and A549 cells were cultured and treated with MAM. The NO generation, DNA damage, and protein expression were determined. Results: MAM induced inducible nitric oxide synthase (iNOS)/NO-mediated DNA damage response through activation of MAPKs pathways. MAM induced DNA damage by activating ATM/Chk2. MAM increased iNOS expression, NO production, and MAPKs (JNK1/2, ERK1/2, and p38MAPK) phosphorylation in concentrationand time- dependent manners. Furthermore, iNOS inhibitor 1400W, iNOS siRNA, and NO scavenger hemoglobin (Hb) could significantly reverse MAM-induced DNA damage, ATM/Chk2 activation, NO production, and cell death. In addition, MAPKs inhibitors (SP600125, U0126, and SB203580) reversed MAM-induced cell death and ATM/Chk2 activation. MAM-induced cell death was partially reversed by 1400W and Hb but enhanced by L-arginine. Conclusion: These results suggested that MAM induced iNOS/NO activation and generation mediated by MAPKs pathways, which resulted in DNA damage.
- Subjects :
- 0301 basic medicine
Cancer Research
Programmed cell death
DNA damage
Cell Survival
Nitric Oxide Synthase Type II
Nitric Oxide
Nitric oxide
03 medical and health sciences
chemistry.chemical_compound
Structure-Activity Relationship
Fallopia japonica
Tumor Cells, Cultured
Humans
Cell Proliferation
Pharmacology
A549 cell
biology
Dose-Response Relationship, Drug
Molecular biology
In vitro
Nitric oxide synthase
030104 developmental biology
chemistry
A549 Cells
Cancer cell
biology.protein
Molecular Medicine
Phosphorylation
Mitogen-Activated Protein Kinases
DNA Damage
Naphthoquinones
Subjects
Details
- ISSN :
- 18755992
- Volume :
- 18
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- Anti-cancer agents in medicinal chemistry
- Accession number :
- edsair.doi.dedup.....4aac24beed9420fa3829ab1c45d2e0c1