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Research Articles: Therapeutics, Targets, and Development

Shikonin circumvents cancer drug resistance by induction of a necroptotic death

¹ Cancer Institute, The Second Affiliated Hospital and ² Department of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China

Requests for reprints: Xun Hu, Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, Zhejiang, China. Phone: 86-571-87783656. E-mail: huxun{at}zju.edu.cn

Abstract

Defect in apoptotic signaling and up-regulation of drug transporters in cancer cells significantly limits the effectiveness of cancer chemotherapy. We propose that an agent inducing non-apoptotic cell death may overcome cancer drug resistance and showed that shikonin, a naturally occurring naphthoquinone, induced a cell death in MCF-7 and HEK293 distinct from apoptosis and characterized with (a) a morphology of necrotic cell death; (b) loss of plasma membrane integrity; (c) loss of mitochondrial membrane potentials; (d) activation of autophagy as a downstream consequence of cell death, but not a contributing factor; (e) elevation of reactive oxygen species with no critical roles contributing to cell death; and (f) that the cell death was prevented by a small molecule, necrostatin-1, that specifically prevents cells from necroptosis. The characteristics fully comply with those of necroptosis, a basic cell-death pathway recently identified by Degterev et al. with potential relevance to human pathology. Furthermore, we proved that shikonin showed a similar potency toward drug-sensitive cancer cell lines (MCF-7 and HEK293) and their drug-resistant lines overexpressing P-glycoprotein, Bcl-2, or Bcl-x_L, which account for most of the clinical cancer drug resistance. To our best knowledge, this is the first report to document the induction of necroptosis by a small molecular compound to circumvent cancer drug resistance. [Mol Cancer Ther 2007;6(5):1641–9]

Grant support: National Ministry of Education, China and Li Ka Shing Foundation, Hong Kong Cheung Kong Scholars Programme (X. Hu); China National 863 project 2003AA223071 (X. Hu); and Bureau For Sciences and Technologies grant 2005C23007, Zhejiang Province, China (X. Hu).

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 data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

⁴ Unpublished data.

Received 8/21/06; revised 3/22/07; accepted 3/30/07.

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