Alantolactone induces apoptosis in chronic myelogenous leukemia sensitive or resistant to imatinib through NF-κB inhibition and Bcr/Abl protein deletion.

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.

• Authors: Wei Wei, He Huang, Shan Zhao, Wei Liu, Chuan-Xu Liu, Li Chen, Jun-Min Li, Ying-Li Wu, Hua Yan
• Journal: Apoptosis : an international journal on programmed cell death (Apoptosis) Vol. 18 Issue 9 Pg. 1060-70 (Sep 2013) ISSN: 1573-675X [Electronic] Netherlands
• PMID: 23613107 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzamides
• Lactones
• NF-kappa B
• Piperazines
• Pyrimidines
• Sesquiterpenes, Eudesmane
• Imatinib Mesylate
• Fusion Proteins, bcr-abl
• alantolactone

Topics

• Animals
• Apoptosis (drug effects)
• Benzamides (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Resistance, Neoplasm
• Fusion Proteins, bcr-abl (genetics)
• Gene Deletion
• Humans
• Imatinib Mesylate
• Lactones (pharmacology)
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, genetics, metabolism)
• Mice
• NF-kappa B (antagonists & inhibitors, genetics, metabolism)
• Piperazines (pharmacology)
• Pyrimidines (pharmacology)
• Sesquiterpenes, Eudesmane (pharmacology)
• Signal Transduction (drug effects)