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Shikonin circumvents cancer drug resistance by induction of a necroptotic death
- Source :
- Molecular cancer therapeutics. 6(5)
- Publication Year :
- 2007
-
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-xL, 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]
- Subjects :
- Cancer Research
Programmed cell death
Necrosis
Necroptosis
Mice, Nude
Antineoplastic Agents
Drug resistance
Biology
Pharmacology
Mice
medicine
Animals
Humans
Cell Death
Dose-Response Relationship, Drug
Autophagy
HEK 293 cells
Anti-Inflammatory Agents, Non-Steroidal
Gene Expression Regulation, Neoplastic
Oncology
Apoptosis
Drug Resistance, Neoplasm
Cancer cell
Cancer research
Female
medicine.symptom
Neoplasm Transplantation
HeLa Cells
Naphthoquinones
Subjects
Details
- ISSN :
- 15357163
- Volume :
- 6
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Molecular cancer therapeutics
- Accession number :
- edsair.doi.dedup.....ef578121fc60e3e5f3e846d50e31f45f