2-Methoxy-6-Acetyl-7-Methyljuglone (MAM) Induces iNOS/NO-mediated DNA Damage Response through Activation of MAPKs Pathways

Author(s): Yanan Niu , Renyikun Yuan , Hongwei Gao , Jin-Jian Lu , Qi Kong , Xiuping Chen* .

Journal Name: Anti-Cancer Agents in Medicinal Chemistry

Volume 18 , Issue 6 , 2018

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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.

Keywords: MAM, DNA damage, iNOS/NO, MAPKs, ATM/Chk2, L-arginine.

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Article Details

VOLUME: 18
ISSUE: 6
Year: 2018
Page: [903 - 913]
Pages: 11
DOI: 10.2174/1871520618666180411111950
Price: $58

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