Shikonin circumvents cancer drug resistance by induction of a necroptotic death.
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| 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.
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| Authors | Weidong Han, Ling Li, Shuang Qiu, Qinghua Lu, Qiangrong Pan, Ying Gu, Jianhong Luo, Xun Hu |
| Journal | Molecular cancer therapeutics (Mol Cancer Ther) Vol. 6 Issue 5 Pg. 1641-9 (May 2007) ISSN: 1535-7163 [Print] United States |
| PMID | 17513612 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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