A new arylbenzofuran derivative functions as an anti-tumour agent by inducing DNA damage and inhibiting PARP activity.

Hongbo Chen,Lanzhen Zhou,Caiping Guo,Laiqiang Huang,Chunmei Gao,Xiangjiu He,Yin Lu,Pinghong Ming,Lin Mei,Xiaobin Zeng,Jianping Zhang,Lijun Wang

doi:10.1038/srep10893

Abstract

We previously reported that 7-hydroxy-5, 4’-dimethoxy-2-arylbenzofuran (HDAB) purified from Livistona chinensis is a key active agent. The present study investigated the function and molecular mechanism of HDAB. HDAB treatment of cervical cancer cells resulted in S phase arrest and apoptosis, together with cyclin A2 and CDK2 upregulation. Cyclin A2 siRNA and a CDK inhibitor efficiently relieved S phase arrest but increased the apoptosis rate. Mechanistic studies revealed that HDAB treatment significantly increased DNA strand breaks in an alkaline comet assay and induced ATM, CHK1, CHK2 and H2A.X phosphorylation. Wortmannin (a broad inhibitor of PIKKs) and CGK733 (a specific ATM inhibitor), but not LY294002 (a phosphatidylinositol 3-kinase inhibitor) or NU7026 (a DNA-PK specific inhibitor), prevented H2A.X phosphorylation and γH2A.X-positive foci formation in the nuclei, reversed S phase arrest and promoted the HDAB-induced apoptosis, suggesting that HDAB is a DNA damaging agent that can activate the ATM-dependent DNA repair response, thereby contributing to cell cycle arrest. In addition, molecular docking and in vitro activity assays revealed that HDAB can correctly dock into the hydrophobic pocket of PARP-1 and suppress PARP-1 ADP-ribosylation activity. Thus, the results indicated that HDAB can function as an anti-cancer agent by inducing DNA damage and inhibiting PARP activity.

Highlights

IntroductionCurrent therapeutic regimens for cervical cancer include surgical removal, radiotherapy and chemotherapy
HDAB is a novel natural product isolated from L. chinensis that has potential antitumour activity against many types of cancer, cervical cancer (Table 1)
The current study showed that treating HeLa and CaSki cells with HDAB resulted in S phase arrest, cell growth inhibition and apoptosis (Figs. 2 and 3)

Summary

Introduction

Current therapeutic regimens for cervical cancer include surgical removal, radiotherapy and chemotherapy. The common combination therapy has a maximum response rate of only 30%, and patients with cervical cancer have a median overall survival of less than 17 months due to the lack of an effective chemotherapy regimen[9]. A genus of approximately 36 species of palms, is widely distributed in southern and southeastern Asia, Australasia, and the Horn of Africa[10]. Their fruits have been used for analgesic and haemostatic purposes in traditional Chinese medicine. The activity of HDAB and the mechanisms by which it exerts its anti-proliferative effects were further investigated

Methods

Results

Conclusion