Lasiodin inhibits proliferation of human nasopharyngeal carcinoma cells by simultaneous modulation of the Apaf-1/caspase, AKT/MAPK and COX-2/NF-κB signaling pathways.

Lianzhu Lin,Lingyi Fu,Wuguo Deng,Mouming Zhao,Wei Luo,Dingbo Shi,Jingshu Wang,Yun Tian,Wangbing Chen,Salvatore V Pizzo

doi:10.1371/journal.pone.0097799

Abstract

Rabdosia serra has been widely used for the treatment of the various human diseases. However, the antiproliferative effects and underlying mechanisms of the compounds in this herb remain largely unknown. In this study, an antiproliferative compound against human nasopharyngeal carcinoma (NPC) cells from Rabdosia serra was purified and identified as lasiodin (a diterpenoid). The treatment with lasiodin inhibited cell viability and migration. Lasiodin also mediated the cell morphology change and induced apoptosis in NPC cells. The treatment with lasiodin induced the Apaf-1 expression, triggered the cytochrome-C release, and stimulated the PARP, caspase-3 and caspase-9 cleavages, thereby activating the apoptotic pathways. The treatment with lasiodin also significantly inhibited the phosphorylations of the AKT, ERK1/2, p38 and JNK proteins. The pretreatment with the AKT or MAPK-selective inhibitors considerably blocked the lasiodin-mediated inhibition of cell proliferation. Moreover, the treatment with lasiodin inhibited the COX-2 expression, abrogated NF-κB binding to the COX-2 promoter, and promoted the NF-κB translocation from cell nuclei to cytosol. The pretreatment with a COX-2-selective inhibitor abrogated the lasiodin-induced inhibition of cell proliferation. These results indicated that lasiodin simultaneously activated the Apaf-1/caspase-dependent apoptotic pathways and suppressed the AKT/MAPK and COX-2/NF-κB signaling pathways. This study also suggested that lasiodin could be a promising natural compound for the prevention and treatment of NPC.

Highlights

Nasopharyngeal carcinoma (NPC) is an unique type of the head and neck cancer, which is a common malignancy in southern China and Southeast Asia [1]
Its chemical structure was further identified by electrospray ionization (ESI)-MS and NMR analysis
The results showed that lasiodin significantly inhibited the binding of p50, p65 and p75 to the COX-2 promoter probe (Figure 6C)

Summary

Introduction

Nasopharyngeal carcinoma (NPC) is an unique type of the head and neck cancer, which is a common malignancy in southern China and Southeast Asia [1]. NPC is associated with a high metastasis rate. It is radiosensitive [2]. The current therapeutic strategies for promoting the local control of advanced NPC led to the acute toxicity and even increased the incidence of the late complications without the survival benefits [2]. Chemotherapy is one of the most extensively studied treatments in anticancer therapies. The combination of chemotherapy and radiotherapy for the NPC treatment may enhance the effects of radiotherapy alone. This strategy may be feasible in patients with locally advanced NPC

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Results

Conclusion