期刊
JOURNAL OF PERSONALIZED MEDICINE
卷 12, 期 1, 页码 -出版社
MDPI
DOI: 10.3390/jpm12010042
关键词
K562 cells; paraptosis; programmed necrosis; COL-3; m-calpain
资金
- Center for Innovative Medicine, Region Stockholm [20200788]
- Swedish Childhood Cancer Foundation (Barncancerfonden) [PR2017-0083, PR2020-0151]
- Cancer Foundation (Cancerfonden) [CAN2014/759, CAN2011/595]
- KI funds [2018-02377]
- Cancer Research Funds of the Radiumhemmet project [161082]
This study investigated the mechanisms of COL-3-induced cytotoxicity in a chronic myeloid leukemia cell line, revealing that it involves DNA damage, mitochondrial and ER perturbation, and features of paraptosis and programmed necrosis.
Tetracycline-3 (4-dedimethylamino sancycline, COL-3) is a non-antibiotic tetracycline derivative. COL-3 exerts potent anti-metalloproteinase activity and its antitumor effects have been reported both in vitro and in vivo. In this study, we investigated the mechanisms of COL-3-induced cytotoxicity in a chronic myeloid leukemia cell line, K562, characterized by the BCR-ABL fusion protein. COL-3 induced K562 cell death in a concentration-dependent manner with an IC50 of 10.8 mu g/mL and exhibited features of both apoptosis and necrosis. However, flow cytometry analysis revealed that necrotic cells dominated over the early and late apoptotic cells upon treatment with COL-3. Transmission electron microscopy analysis in combination with Western blotting (WB) analysis revealed early mitochondrial swelling accompanied by the early release of cytochrome c and truncated apoptosis inducing factor (tAIF). In addition, ultrastructural changes were detected in the endoplasmic reticulum (ER). COL-3 affected the levels of glucose-regulated protein-94 (GRP94) and resulted in m-calpain activation. DNA double strand breaks as a signature for DNA damage was also confirmed using an antibody against gamma H2AX. WB analyses did not demonstrate caspase activation, while Bcl-xL protein remained unaffected. In conclusion, COL-3-induced cell death involves DNA damage as well as mitochondrial and ER perturbation with features of paraptosis and programmed necrosis.
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