Journal
APOPTOSIS
Volume 18, Issue 9, Pages 1060-1070Publisher
SPRINGER
DOI: 10.1007/s10495-013-0854-2
Keywords
Alantolactone; Chronic myelogenous leukemia; Apoptosis; Bcr/Abl; NF-kappa B
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Funding
- National Basic Research Program of China (973 Program) [2010CB912104]
- National Natural Science Foundation [81170509, 81070433, 91013008, 81272886, 30570777]
- Science and Technology Committee of Shanghai [11JC1406500]
- SMC Program of Shanghai Jiao Tong University
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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-kappa B-dependent reporter gene activity, decreased the DNA-binding activity of NF-D kappa B, and blocked TNF-alpha-induced I kappa B alpha 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-kappa B signaling pathway and depletion of the Bcr/Abl protein.
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