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

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

Volume: 18 Issue: 6

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

Affiliation:

• State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao,China

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

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.

Cite this article as:

Niu Yanan , Yuan Renyikun , Gao Hongwei , Lu Jin-Jian , Kong Qi and Chen Xiuping*, 2-Methoxy-6-Acetyl-7-Methyljuglone (MAM) Induces iNOS/NO-mediated DNA Damage Response through Activation of MAPKs Pathways, Anti-Cancer Agents in Medicinal Chemistry 2018; 18 (6) . https://dx.doi.org/10.2174/1871520618666180411111950