Antileukemia effects of xanthohumol in Bcr/Abl-transformed cells involve nuclear factor-kappaB and p53 modulation.
The oncogenic Bcr-Abl tyrosine kinase activates various signaling pathways including phosphoinositide 3-kinase/Akt and nuclear factor-kappaB that mediate proliferation, transformation, and apoptosis resistance in Bcr-Abl+ myeloid leukemia cells. The hop flavonoid xanthohumol inhibits tumor growth by targeting the nuclear factor-kappaB and Akt pathways and angiogenesis. Here, we show that xanthohumol has in vitro activity against Bcr-Abl+ cells and clinical samples and retained its cytotoxicity when imatinib mesylate-resistant K562 cells were examined. Xanthohumol inhibition of K562 cell viability was associated with induction of apoptosis, increased p21 and p53 expression, and decreased survivin levels. We show that xanthohumol strongly inhibited Bcr-Abl expression at both mRNA and protein levels and show that xanthohumol caused elevation of intracellular reactive oxygen species and that the antioxidant N-acetylcysteine blunted xanthohumol-induced events. Further, we observed that xanthohumol inhibits leukemia cell invasion, metalloprotease production, and adhesion to endothelial cells, potentially preventing in vivo life-threatening complications of leukostasis and tissue infiltration by leukemic cells. As structural mutations and/or gene amplification in Bcr-Abl can circumvent an otherwise potent anticancer drug such as imatinib, targeting Bcr-Abl expression as well as its kinase activity could be a novel additional therapeutic approach for the treatment of Bcr-Abl+ myeloid leukemia.
Monteghirfo
Stefano
S
Oncologia Molecolare, Istituto Nazionale per la Ricerca sul Cancro, L.go R.Benzi, 10, 16132 Genova, Italy.
Tosetti
Francesca
F
Ambrosini
Claudia
C
Stigliani
Sara
S
Pozzi
Sarah
S
Frassoni
Francesco
F
Fassina
Gianfranco
G
Soverini
Simona
S
Albini
Adriana
A
Ferrari
Nicoletta
N
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001549:Benzamides; D002448:Cell Adhesion / Q000187:drug effects; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005419:Flavonoids; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D011427:Propiophenones / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D020298:U937 Cells; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D000970:Antineoplastic Agents; D001549:Benzamides; D005419:Flavonoids; D016328:NF-kappa B; D010879:Piperazines; D011427:Propiophenones; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; C104536:xanthohumol