title: Shikonin circumvents cancer drug resistance by induction of a necroptotic death.
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.
authors.affiliation: Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, Zhejiang, China.
authors.forename: Weidong
authors.initials: W
authors.lastname: Han
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.forename: Shuang
authors.initials: S
authors.lastname: Qiu
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Lu
authors.forename: Qiangrong
authors.initials: Q
authors.lastname: Pan
authors.forename: Ying
authors.initials: Y
authors.lastname: Gu
authors.forename: Jianhong
authors.initials: J
authors.lastname: Luo
authors.forename: Xun
authors.initials: X
authors.lastname: Hu
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D016923:Cell Death; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009285:Naphthoquinones / Q000494:pharmacology*; D009336:Necrosis; D009368:Neoplasm Transplantation
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D009285:Naphthoquinones; C016101:shikonin