Shikonin circumvents cancer drug resistance by induction of a necroptotic death

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.