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2-Methoxy-6-Acetyl-7-Methyljuglone (MAM) Induces iNOS/NO-mediated DNA Damage Response through Activation of MAPKs
Yanan Niu1,2, Renyikun Yuan1, Hongwei Gao1
1State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
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.
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