Antileukemia effects of xanthohumol in Bcr/Abl-transformed cells involve nuclear factor-κB and p53 modulation

Stefano Monteghirfo, Francesca Tosetti, Claudia Ambrosini, Sara Stigliani, Sarah Pozzi, Francesco Frassoni, Gianfranco Fassina, Simona Soverini, Adriana Albini, Nicoletta Ferrari

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

The oncogenic Bcr-Abl tyrosine kinase activates various signaling pathways including phosphoinositide 3-kinase/Akt and nuclear factor-κB 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-κB 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 suchas 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.

Original languageEnglish
Pages (from-to)2692-2702
Number of pages11
JournalMolecular Cancer Therapeutics
Volume7
Issue number9
DOIs
Publication statusPublished - 2008

Fingerprint

Myeloid Leukemia
K562 Cells
Leukostasis
bcr-abl Fusion Proteins
Leukemic Infiltration
Apoptosis
Humulus
1-Phosphatidylinositol 4-Kinase
Gene Amplification
Acetylcysteine
Metalloproteases
Myeloid Cells
xanthohumol
Flavonoids
Reactive Oxygen Species
Cell Survival
Leukemia
Phosphotransferases
Endothelial Cells
Antioxidants

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Antileukemia effects of xanthohumol in Bcr/Abl-transformed cells involve nuclear factor-κB and p53 modulation. / Monteghirfo, Stefano; Tosetti, Francesca; Ambrosini, Claudia; Stigliani, Sara; Pozzi, Sarah; Frassoni, Francesco; Fassina, Gianfranco; Soverini, Simona; Albini, Adriana; Ferrari, Nicoletta.

In: Molecular Cancer Therapeutics, Vol. 7, No. 9, 2008, p. 2692-2702.

Research output: Contribution to journalArticle

Monteghirfo, Stefano ; Tosetti, Francesca ; Ambrosini, Claudia ; Stigliani, Sara ; Pozzi, Sarah ; Frassoni, Francesco ; Fassina, Gianfranco ; Soverini, Simona ; Albini, Adriana ; Ferrari, Nicoletta. / Antileukemia effects of xanthohumol in Bcr/Abl-transformed cells involve nuclear factor-κB and p53 modulation. In: Molecular Cancer Therapeutics. 2008 ; Vol. 7, No. 9. pp. 2692-2702.
@article{ed433daa24b54da1996a020574904ff0,
title = "Antileukemia effects of xanthohumol in Bcr/Abl-transformed cells involve nuclear factor-κB and p53 modulation",
abstract = "The oncogenic Bcr-Abl tyrosine kinase activates various signaling pathways including phosphoinositide 3-kinase/Akt and nuclear factor-κB 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-κB 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 suchas 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.",
author = "Stefano Monteghirfo and Francesca Tosetti and Claudia Ambrosini and Sara Stigliani and Sarah Pozzi and Francesco Frassoni and Gianfranco Fassina and Simona Soverini and Adriana Albini and Nicoletta Ferrari",
year = "2008",
doi = "10.1158/1535-7163.MCT-08-0132",
language = "English",
volume = "7",
pages = "2692--2702",
journal = "Molecular Cancer Therapeutics",
issn = "1535-7163",
publisher = "American Association for Cancer Research Inc.",
number = "9",

}

TY - JOUR

T1 - Antileukemia effects of xanthohumol in Bcr/Abl-transformed cells involve nuclear factor-κB and p53 modulation

AU - Monteghirfo, Stefano

AU - Tosetti, Francesca

AU - Ambrosini, Claudia

AU - Stigliani, Sara

AU - Pozzi, Sarah

AU - Frassoni, Francesco

AU - Fassina, Gianfranco

AU - Soverini, Simona

AU - Albini, Adriana

AU - Ferrari, Nicoletta

PY - 2008

Y1 - 2008

N2 - The oncogenic Bcr-Abl tyrosine kinase activates various signaling pathways including phosphoinositide 3-kinase/Akt and nuclear factor-κB 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-κB 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 suchas 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.

AB - The oncogenic Bcr-Abl tyrosine kinase activates various signaling pathways including phosphoinositide 3-kinase/Akt and nuclear factor-κB 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-κB 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 suchas 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.

UR - http://www.scopus.com/inward/record.url?scp=54049094848&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=54049094848&partnerID=8YFLogxK

U2 - 10.1158/1535-7163.MCT-08-0132

DO - 10.1158/1535-7163.MCT-08-0132

M3 - Article

C2 - 18790751

AN - SCOPUS:54049094848

VL - 7

SP - 2692

EP - 2702

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

SN - 1535-7163

IS - 9

ER -