Effusanin E suppresses nasopharyngeal carcinoma cell growth by inhibiting NF-κB and COX-2 signaling.

Mingzhu Zhuang,Mouming Zhao,Wuguo Deng,Huijuan Qiu,Jingshu Wang,Lianzhu Lin,Dingbo Shi,Yun Tian,Peiwen Fei

doi:10.1371/journal.pone.0109951

Abstract

Rabdosia serra is well known for its antibacterial, anti-inflammatory and antitumor activities, but no information has been available for the active compounds derived from this plant in inhibiting human nasopharyngeal carcinoma (NPC) cell growth. In this study, we isolated and purified a natural diterpenoid from Rabdosia serra and identified its chemical structure as effusanin E and elucidated its underlying mechanism of action in inhibiting NPC cell growth. Effusanin E significantly inhibited cell proliferation and induced apoptosis in NPC cells. Effusanin E also induced the cleavage of PARP, caspase-3 and -9 proteins and inhibited the nuclear translocation of p65 NF-κB proteins. Moreover, effusanin E abrogated the binding of NF-κB to the COX-2 promoter, thereby inhibiting the expression and promoter activity of COX-2. Pretreatment with a COX-2 or NF-κB-selective inhibitor (celecoxib or ammonium pyrrolidinedithiocarbamate) had an additive effect on the effusanin E-mediated inhibition of proliferation, while pretreatment with an activator of NF-κB/COX-2 (lipopolysaccharides) abrogated the effusanin E-mediated inhibition of proliferation. Effusanin E also significantly suppressed tumor growth in a xenograft mouse model without obvious toxicity, furthermore, the expression of p50 NF-κB and COX-2 were down-regulated in the tumors of nude mice. These data suggest that effusanin E suppresses p50/p65 proteins to down-regulate COX-2 expression, thereby inhibiting NPC cell growth. Our findings provide new insights into exploring effusanin E as a potential therapeutic compound for the treatment of human nasopharyngeal carcinoma.

Highlights

Nasopharyngeal carcinoma (NPC) is a relatively uncommon, malignant, head and neck cancer that is found worldwide but is highly prevalent in South China and Southeast Asia [1]
We further examined whether the inhibition of COX-2 signaling by effusanin E was mediated through NF-kB signaling in NPC cells
We demonstrate that effusanin E inhibited the proliferation and induced apoptosis of NPC cells in vitro

Summary

Introduction

Nasopharyngeal carcinoma (NPC) is a relatively uncommon, malignant, head and neck cancer that is found worldwide but is highly prevalent in South China and Southeast Asia [1]. It frequently occurs in the Guangdong area, China, where the annual incidence reaches 25 cases per 100,000 [2]. The 5-year survival rate is only 50– 60% due to the frequency of distant metastasis and local recurrence and the long-term secondary effects of radiotherapy and chemotherapy [3] These methods may sometimes cause severe acute toxicity and even increased incidence of late complications without obvious survival benefits [4]. The use of natural, synthetic or biologic chemicals has been considered as effective cancer chemopreventions in the prevention, suppression or delay of the carcinogenesis process [5]

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