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Alantolactone induces apoptosis in chronic myelogenous leukemia sensitive or resistant to imatinib through NF-κB inhibition and Bcr/Abl protein deletion.
- Source :
-
Apoptosis : an international journal on programmed cell death [Apoptosis] 2013 Sep; Vol. 18 (9), pp. 1060-70. - Publication Year :
- 2013
-
Abstract
- Alantolactone, an allergenic sesquiterpene lactone, has recently been found to have significant antitumor effects on malignant tumor cells. Here, we investigated the potential effect of alantolactone on Bcr/Abl+ imatinib-sensitive and -resistant cells. Alantolactone treatment resulted in obvious apoptosis in both imatinib-sensitive and -resistant K562 cells, as shown by the increase in Annexin V-positive cells, caspase-3 activation, poly(ADP-ribose) polymerase-1 (PARP-1) cleavage and mitochondrial membrane potential collapse. Alantolactone significantly inhibited NF-κB-dependent reporter gene activity, decreased the DNA-binding activity of NF-ОκB, and blocked TNF-α-induced IκBα phosphorylation. Of interest, the oncogenic Bcr/Abl fusion protein but not its mRNA levels were quickly reduced upon alantolactone exposure in imatinib-sensitive and -resistant K562 cells. Bcr/Abl knockdown enhanced the apoptosis driven by alantolactone. Bcr/Abl protein reduction could not be reversed by the addition of proteasome or caspase-3 inhibitors. The overexpression of p65 inhibited alantolactone-induced apoptosis, whereas p65 or Bcr/Abl silencing enhanced its apoptotic-inducing effect. Furthermore, Bcr/Abl-transfected 32D cells showed more sensitivity to alantolactone than vector-transfected control cells, and the Bcr/Abl protein was depleted, as observed in K562 cells. Finally, alantolactone-induced apoptosis was also observed in primary CD34+ CML leukemic cells. Collectively, these findings suggest that alantolactone is a promising potent agent to fight against CML cells via the inhibition of the NF-κB signaling pathway and depletion of the Bcr/Abl protein.
- Subjects :
- Animals
Cell Line, Tumor
Cell Proliferation drug effects
Humans
Imatinib Mesylate
Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy
Leukemia, Myelogenous, Chronic, BCR-ABL Positive metabolism
Mice
NF-kappa B genetics
NF-kappa B metabolism
Signal Transduction drug effects
Apoptosis drug effects
Benzamides pharmacology
Drug Resistance, Neoplasm
Fusion Proteins, bcr-abl genetics
Gene Deletion
Lactones pharmacology
Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics
NF-kappa B antagonists & inhibitors
Piperazines pharmacology
Pyrimidines pharmacology
Sesquiterpenes, Eudesmane pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1573-675X
- Volume :
- 18
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Apoptosis : an international journal on programmed cell death
- Publication Type :
- Academic Journal
- Accession number :
- 23613107
- Full Text :
- https://doi.org/10.1007/s10495-013-0854-2