Journal ArticleDOI
Shikonin circumvents cancer drug resistance by induction of a necroptotic death.
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TLDR
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, loss of mitochondrial membrane potentials, activation of autophagy, but not a contributing factor; (e) elevation of reactive oxygen species with no critical roles contributing to cell death; and (f) the cell death was prevented by a small molecule, necrostatin-1, that specificallyAbstract:
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.read more
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Journal ArticleDOI
Immunogenic cell death and DAMPs in cancer therapy.
Dmitri V. Krysko,Abhishek D. Garg,Agnieszka Kaczmarek,Olga Krysko,Patrizia Agostinis,Peter Vandenabeele +5 more
TL;DR: The role of endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) in regulating the immunogenicity of dying cancer cells and the effect of therapy-resistant cancer microevolution on ICD are discussed.
Journal ArticleDOI
Regulated necrosis: the expanding network of non-apoptotic cell death pathways
Tom Vanden Berghe,Andreas Linkermann,Sandrine Jouan-Lanhouet,Henning Walczak,Peter Vandenabeele +4 more
TL;DR: Elucidating how these pathways of regulated necrosis are interconnected at the molecular level should enable this process to be therapeutically targeted.
Journal ArticleDOI
Cell death: a review of the major forms of apoptosis, necrosis and autophagy
TL;DR: The goal of this review is to provide a general overview of the current knowledge relating to the various forms of cell death, including apoptosis, necrosis, oncosis, pyroptosis and autophagy.
Journal ArticleDOI
Identification of a Molecular Signaling Network that Regulates a Cellular Necrotic Cell Death Pathway
Junichi Hitomi,Dana E. Christofferson,Aylwin Ng,Jianhua Yao,Alexei Degterev,Ramnik J. Xavier,Junying Yuan +6 more
TL;DR: A cellular signaling network that regulates necroptosis and the molecular bifurcation that controls apoptosis and ne croptosis is defined and it is shown that the expression of subsets of the 432 genes is enriched in the immune and nervous systems, and cellular sensitivity to necroPTosis is regulated by an extensive signaling network mediating innate immunity.
Journal ArticleDOI
Apoptosis, autophagy, necroptosis, and cancer metastasis
TL;DR: This review summarizes the recent advances in the understanding of the mechanisms by which key regulators of apoptosis, autophagy, and necroptosis participate in cancer metastasis and discusses the crosstalk between apoptosis-autophagy-and-novoptosis involved in the regulation of cancer metastatic processes.
References
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Journal ArticleDOI
Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury
Alexei Degterev,Zhihong Huang,Michael Boyce,Yaqiao Li,Prakash Jagtap,Noboru Mizushima,Gregory D. Cuny,Timothy J. Mitchison,Michael A. Moskowitz,Junying Yuan +9 more
TL;DR: It is demonstrated that necroptosis contributes to delayed mouse ischemic brain injury in vivo through a mechanism distinct from that of apoptosis and offers a new therapeutic target for stroke with an extended window for neuroprotection.
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A Family of Drug Transporters: the Multidrug Resistance-Associated Proteins
TL;DR: Whether long-term inhibition of MRPs in humans can be tolerated (assuming that suitable inhibitors will be found) remains to be determined.
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Molecular mechanisms of drug resistance
TL;DR: The signalling pathways involved in regulating tumour cell response to chemotherapy more completely than ever before are characterized, which will facilitate the future development of rational combined chemotherapy regimens, in which the newer targeted therapies are used in combination with cytotoxic drugs to enhance chemotherapy activity.
Journal ArticleDOI
Regulation of an ATG7-beclin 1 Program of Autophagic Cell Death by Caspase-8
Li Yu,Ajjai Alva,Helen C. Su,Parmesh Dutt,Eric C. Freundt,Eric C. Freundt,Sarah Welsh,Eric H. Baehrecke,Michael J. Lenardo +8 more
TL;DR: A new molecular pathway in which activation of the receptor-interacting protein (a serine-threonine kinase) and Jun amino-terminal kinase induced cell death with the morphology of autophagy is defined.
Journal ArticleDOI
The role of apoptosis in cancer development and treatment response.
J. Martin Brown,Laura D. Attardi +1 more
TL;DR: This work has shown that in many tumours, apoptosis is not the main mechanism for the death of cancer cells in response to common treatment regimens, suggesting that other modes of cell death are involved in the response to therapy.