Mitochondrial targeting domain of NOXA causes necrosis in apoptosis-resistant tumor cells

The resistance of tumor cells to apoptosis-inducing anticancer agents is regarded as a major impediment for the treatment of cancer patients. This study aimed to examine the possibility whether a necrosis-inducing peptide containing the mitochondria-targeting domain (MTD) of NOXA kills tumor cells t...

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Bibliographic Details
Published in:Amino acids 2018-12, Vol.50 (12), p.1707-1717
Main Authors: Nguyen, Dai-Trang, He, Siyuan, Han, Ji-Hye, Park, Junghee, Seo, Young-Woo, Kim, Tae-Hyoung
Format: Article
Language:English
Subjects:
Analytical Chemistry
Animals
Anticancer properties
Antitumor agents
Apoptosis
Apoptosis - drug effects
Arginine
Biochemical Engineering
Biochemistry
Biomedical and Life Sciences
Calcium Signaling - drug effects
Calcium signalling
Cancer
Cell activation
Cell Line, Tumor
Doxorubicin
Doxorubicin - pharmacology
Drug Resistance, Neoplasm - drug effects
Gangrene
Humans
Life Sciences
Mice, Inbred BALB C
Mitochondria
Mitochondria - drug effects
Necrosis
Neurobiology
Original Article
Peptide Fragments - chemistry
Peptide Fragments - pharmacology
Peptides
Proteomics
Proto-Oncogene Proteins c-bcl-2 - chemistry
Proto-Oncogene Proteins c-bcl-2 - pharmacology
Reactive oxygen species
Reactive Oxygen Species - metabolism
Tumor cells
Tumors
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Summary:The resistance of tumor cells to apoptosis-inducing anticancer agents is regarded as a major impediment for the treatment of cancer patients. This study aimed to examine the possibility whether a necrosis-inducing peptide containing the mitochondria-targeting domain (MTD) of NOXA kills tumor cells that are resistant to apoptosis-inducing anticancer agents. To examine this possibility, we established doxorubicin-resistant (Dox-Res) cells by treating CT26 cells with increasing amounts of doxorubicin. The apoptosis resistance of the Dox-Res CT26 cells was confirmed by measuring the cell viability and activation of caspases. We showed that the MTD-containing peptide fused to eight arginine residues (R8:MTD), a necrosis-inducing peptide, induced necrosis in the Dox-Res CT26 cells, together with a cytosolic calcium spike, reactive oxygen species production, and the release of high mobility group box 1 into the media. Moreover, we demonstrated the killing effect of R8:MTD in tumor tissues generated using the Dox-Res CT26 cells in a mouse model. Therefore, our results suggest that MTD-containing peptides may provide an alternative tool for the elimination of relapsed tumor cells that are not responsive to apoptosis-inducing anticancer agents.
ISSN:0939-4451
1438-2199
DOI:10.1007/s00726-018-2644-1