title: 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.affiliation: Department of Hematology, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, No. 197, Ruijin Er Road, Shanghai, 200025, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.forename: He
authors.initials: H
authors.lastname: Huang
authors.forename: Shan
authors.initials: S
authors.lastname: Zhao
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Chuan-Xu
authors.initials: CX
authors.lastname: Liu
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.forename: Jun-Min
authors.initials: JM
authors.lastname: Li
authors.forename: Ying-Li
authors.initials: YL
authors.lastname: Wu
authors.forename: Hua
authors.initials: H
authors.lastname: Yan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D017353:Gene Deletion; D006801:Humans; D000068877:Imatinib Mesylate; D007783:Lactones / Q000494:pharmacology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D045787:Sesquiterpenes, Eudesmane / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D001549:Benzamides; D007783:Lactones; D016328:NF-kappa B; D010879:Piperazines; D011743:Pyrimidines; D045787:Sesquiterpenes, Eudesmane; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; C004363:alantolactone