The AKT/NF-κB inhibitor xanthohumol is a potent anti-lymphocytic leukemia drug overcoming chemoresistance and cell infiltration

Roberto Benelli, Roberta Ven, Monica Ciarlo, Sebastiano Carlone, Ottavia Barbieri, Nicoletta Ferrari

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Although the vast majority of patients with acute lymphocytic leukemia (ALL) attain remission with modern therapies, relapsed leukemia will continue to be a common malignancy both in childhood and in adults, until new treatments are available. Therapeutic options for advanced B-cell acute lymphocytic leukemia are still limited and acquired drug resistance and extramedullary tissue infiltration are two major obstacles during treatment. The prenylflavonoid xanthohumol (XN) has shown in vitro and in vivo therapeutic potential against a range of tumors. In the present study we investigated the effects of XN on B-ALL cells in vitro and in an ALL-like xenograft mouse model. Treatment of ALL cell lines with XN resulted in growth arrest and apoptosis induction. XN retained its cytotoxicity when adriamycin resistant cells were examined while ALL cell clones adapted to long-term exposure to XN resulted highly responsive to cytotoxic drugs. Administration of 50 μg XN/mouse (5 days/week) significantly increased animal life span by delaying the insurgence of neurological disorders due to leukemic cells dissemination. In agreement with a less invasive phenotype, cell migration and invasion were impaired by XN and basal levels of FAK, AKT and NF-κB signaling pathways were down-regulated in ALL cells upon XN exposure. Our data indicate that XN has significant antileukemic activity both in vitro and in vivo, which associates with impaired cell migration and invasion. Interestingly, this activity overcomes mechanisms leading to drug-resistance. XN represents a promising agent perspective for ALL therapy and recurrence prevention and would deserve clinical testing in the near future.

Original languageEnglish
Pages (from-to)1634-1642
Number of pages9
JournalBiochemical Pharmacology
Volume83
Issue number12
DOIs
Publication statusPublished - Jun 15 2012

Fingerprint

Lymphoid Leukemia
Infiltration
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Pharmaceutical Preparations
B-Cell Leukemia
Drug Resistance
Therapeutics
Cell Movement
Clone cells
Cells
xanthohumol
Cytotoxicity
Nervous System Diseases
Heterografts
Doxorubicin
Tumors
Neoplasms
Leukemia
Animals
Clone Cells

Keywords

  • ALL
  • Chemoprevention
  • Chemoresistance
  • Migration
  • Xanthohumol

ASJC Scopus subject areas

  • Pharmacology
  • Biochemistry

Cite this

The AKT/NF-κB inhibitor xanthohumol is a potent anti-lymphocytic leukemia drug overcoming chemoresistance and cell infiltration. / Benelli, Roberto; Ven, Roberta; Ciarlo, Monica; Carlone, Sebastiano; Barbieri, Ottavia; Ferrari, Nicoletta.

In: Biochemical Pharmacology, Vol. 83, No. 12, 15.06.2012, p. 1634-1642.

Research output: Contribution to journalArticle

@article{b438a89df1bf4590a81f2ae8c4304510,
title = "The AKT/NF-κB inhibitor xanthohumol is a potent anti-lymphocytic leukemia drug overcoming chemoresistance and cell infiltration",
abstract = "Although the vast majority of patients with acute lymphocytic leukemia (ALL) attain remission with modern therapies, relapsed leukemia will continue to be a common malignancy both in childhood and in adults, until new treatments are available. Therapeutic options for advanced B-cell acute lymphocytic leukemia are still limited and acquired drug resistance and extramedullary tissue infiltration are two major obstacles during treatment. The prenylflavonoid xanthohumol (XN) has shown in vitro and in vivo therapeutic potential against a range of tumors. In the present study we investigated the effects of XN on B-ALL cells in vitro and in an ALL-like xenograft mouse model. Treatment of ALL cell lines with XN resulted in growth arrest and apoptosis induction. XN retained its cytotoxicity when adriamycin resistant cells were examined while ALL cell clones adapted to long-term exposure to XN resulted highly responsive to cytotoxic drugs. Administration of 50 μg XN/mouse (5 days/week) significantly increased animal life span by delaying the insurgence of neurological disorders due to leukemic cells dissemination. In agreement with a less invasive phenotype, cell migration and invasion were impaired by XN and basal levels of FAK, AKT and NF-κB signaling pathways were down-regulated in ALL cells upon XN exposure. Our data indicate that XN has significant antileukemic activity both in vitro and in vivo, which associates with impaired cell migration and invasion. Interestingly, this activity overcomes mechanisms leading to drug-resistance. XN represents a promising agent perspective for ALL therapy and recurrence prevention and would deserve clinical testing in the near future.",
keywords = "ALL, Chemoprevention, Chemoresistance, Migration, Xanthohumol",
author = "Roberto Benelli and Roberta Ven and Monica Ciarlo and Sebastiano Carlone and Ottavia Barbieri and Nicoletta Ferrari",
year = "2012",
month = "6",
day = "15",
doi = "10.1016/j.bcp.2012.03.006",
language = "English",
volume = "83",
pages = "1634--1642",
journal = "Biochemical Pharmacology",
issn = "0006-2952",
publisher = "Elsevier Inc.",
number = "12",

}

TY - JOUR

T1 - The AKT/NF-κB inhibitor xanthohumol is a potent anti-lymphocytic leukemia drug overcoming chemoresistance and cell infiltration

AU - Benelli, Roberto

AU - Ven, Roberta

AU - Ciarlo, Monica

AU - Carlone, Sebastiano

AU - Barbieri, Ottavia

AU - Ferrari, Nicoletta

PY - 2012/6/15

Y1 - 2012/6/15

N2 - Although the vast majority of patients with acute lymphocytic leukemia (ALL) attain remission with modern therapies, relapsed leukemia will continue to be a common malignancy both in childhood and in adults, until new treatments are available. Therapeutic options for advanced B-cell acute lymphocytic leukemia are still limited and acquired drug resistance and extramedullary tissue infiltration are two major obstacles during treatment. The prenylflavonoid xanthohumol (XN) has shown in vitro and in vivo therapeutic potential against a range of tumors. In the present study we investigated the effects of XN on B-ALL cells in vitro and in an ALL-like xenograft mouse model. Treatment of ALL cell lines with XN resulted in growth arrest and apoptosis induction. XN retained its cytotoxicity when adriamycin resistant cells were examined while ALL cell clones adapted to long-term exposure to XN resulted highly responsive to cytotoxic drugs. Administration of 50 μg XN/mouse (5 days/week) significantly increased animal life span by delaying the insurgence of neurological disorders due to leukemic cells dissemination. In agreement with a less invasive phenotype, cell migration and invasion were impaired by XN and basal levels of FAK, AKT and NF-κB signaling pathways were down-regulated in ALL cells upon XN exposure. Our data indicate that XN has significant antileukemic activity both in vitro and in vivo, which associates with impaired cell migration and invasion. Interestingly, this activity overcomes mechanisms leading to drug-resistance. XN represents a promising agent perspective for ALL therapy and recurrence prevention and would deserve clinical testing in the near future.

AB - Although the vast majority of patients with acute lymphocytic leukemia (ALL) attain remission with modern therapies, relapsed leukemia will continue to be a common malignancy both in childhood and in adults, until new treatments are available. Therapeutic options for advanced B-cell acute lymphocytic leukemia are still limited and acquired drug resistance and extramedullary tissue infiltration are two major obstacles during treatment. The prenylflavonoid xanthohumol (XN) has shown in vitro and in vivo therapeutic potential against a range of tumors. In the present study we investigated the effects of XN on B-ALL cells in vitro and in an ALL-like xenograft mouse model. Treatment of ALL cell lines with XN resulted in growth arrest and apoptosis induction. XN retained its cytotoxicity when adriamycin resistant cells were examined while ALL cell clones adapted to long-term exposure to XN resulted highly responsive to cytotoxic drugs. Administration of 50 μg XN/mouse (5 days/week) significantly increased animal life span by delaying the insurgence of neurological disorders due to leukemic cells dissemination. In agreement with a less invasive phenotype, cell migration and invasion were impaired by XN and basal levels of FAK, AKT and NF-κB signaling pathways were down-regulated in ALL cells upon XN exposure. Our data indicate that XN has significant antileukemic activity both in vitro and in vivo, which associates with impaired cell migration and invasion. Interestingly, this activity overcomes mechanisms leading to drug-resistance. XN represents a promising agent perspective for ALL therapy and recurrence prevention and would deserve clinical testing in the near future.

KW - ALL

KW - Chemoprevention

KW - Chemoresistance

KW - Migration

KW - Xanthohumol

UR - http://www.scopus.com/inward/record.url?scp=84860146666&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84860146666&partnerID=8YFLogxK

U2 - 10.1016/j.bcp.2012.03.006

DO - 10.1016/j.bcp.2012.03.006

M3 - Article

C2 - 22445931

AN - SCOPUS:84860146666

VL - 83

SP - 1634

EP - 1642

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

IS - 12

ER -