Andrographis News

Andrographolide sensitizes cancer cells to TRAIL-induced apoptosis via p53-mediated death receptor 4 up-regulation

Wednesday, December 24, 2008

Molecular Cancer Therapeutics 7, 2170-2180, July 1, 2008. doi: 10.1158/1535-7163.MCT-08-0071

Jing Zhou¹, Guo-Dong Lu¹, Chye-Sun Ong², Choon-Nam Ong¹ and Han-Ming Shen^1
1 Department of Community, Occupational and Family Medicine, Yong Loo Lin School of Medicine, National University of Singapore; ² School of Chemical & Life Sciences, Singapore Polytechnic, Singapore, Republic of Singapore
Requests for reprints: Han-Ming Shen, Department of Community, Occupational and Family Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Singapore 117597, Republic of Singapore. Phone: 65-6516-4998; Fax: 65-6779-1489. E-mail: cofshm@nus.edu.sg

Abstract
Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is an important member of the tumor necrosis factor subfamily with great potential in cancer therapy. Andrographolide (Andro), a diterpenoid lactone isolated from a traditional herbal medicine Andrographis paniculata, is known to possess potent anti-inflammatory and anticancer activities. Here, we showed that pretreatment with Andro significantly enhances TRAIL-induced apoptosis in various human cancer cell lines, including those TRAIL-resistant cells. Such sensitization is achieved through transcriptional up-regulation of death receptor 4 (DR4), a death receptor of TRAIL. In search of the molecular mechanisms responsible for DR4 up-regulation, we found that the tumor suppressor p53 plays an essential role in DR4 transcriptional activation. Andro is capable of activating p53 via increased p53 phosphorylation and protein stabilization, a process mediated by enhanced reactive oxygen species production and subsequent c-Jun NH₂-terminal kinase activation. Pretreatment with an antioxidant (N-acetylcysteine) or a c-Jun NH₂-terminal kinase inhibitor (SP600125) effectively prevented Andro-induced p53 activation and DR4 up-regulation and eventually blocked the Andro-induced sensitization on TRAIL-induced apoptosis. Taken together, these results present a novel anticancer effect of Andro and support its potential application in cancer therapy to overcome TRAIL resistance. [Mol Cancer Ther 2008;7(7):2170–80]

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