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Research Articles: Therapeutics, Targets, and Development

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

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{at}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]

Grant support: National University of Singapore research scholarship (J. Zhou), Singapore National Medical Research Council research grant NMRC/0949/2005 and Biomedical Research Council research grant BMRC04/1/21/19/333 (H-M. Shen), and Office of Life Science Toxicology Program (H-M. Shen and C-N. Ong).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

³ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 1/21/08; revised 3/10/08; accepted 3/18/08.