Zoledronic acid down-regulates adhesion molecules of bone marrow stromal cells in multiple myeloma: A possible mechanism for its antitumor effect

Alessandro Corso, Eleonora Ferretti, Monia Lunghi, Patrizia Zappasodi, Silvia Mangiacavalli, Mara De Amici, Chiara Rusconi, Marzia Varettoni, Mario Lazzarino

Research output: Contribution to journalArticle

Abstract

BACKGROUND. Myeloma plasma cells interact with the bone marrow microenvironment which, in turn, supports their growth and protects them from apoptosis. In vitro studies have demonstrated the antitumor potential of zoledronic acid (ZOL) on myeloma cell lines, but few data are available on its effects on bone marrow stromal cells (BMSCs). The aim of the current study was to evaluate the antiproliferative and apoptotic effect of ZOL on BMSCs, as well as its effect on the expression of adhesion molecules. METHODS. BMSCs, obtained from bone marrow mononucleated cells of 8 patients with multiple myeloma, were treated with increasing concentrations of ZOL for 3 days. Cytotoxic effect was analyzed by 3-(4-5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide; thiazolyl blue (MTT) assay whereas the induction of apoptosis was evaluated by flow cytometric detection of fluorescein isothiocyanate-labeled annexin V, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay, and nuclear changes. Moreover, expression of CD106, CD56, CD50, CD49d, CD44, and CD40 was analyzed by flow cytometry. Data were evaluated by the Friedman test. RESULTS. After 3 days of exposure at concentrations of 10-4 to 10-5 M, ZOL induced a decrease in proliferation (P <0.0001) and an increase in apoptosis (P <0.002). Analysis of culture supernatants showed that myeloma BMSCs expressed interleukin (IL)-6, negligible levels of tumor necrosis factor-alpha, and no IL-1β. In vitro exposure to the lowest concentrations of ZOL decreased IL-6 production by BMSCs. Among the adhesion molecules, CD106, CD54, CD49d, and CD40, which were strongly expressed at baseline, showed a statistically significant reduction compared with controls after exposure to ZOL. CONCLUSIONS. ZOL interfered with myeloma BMSCs by reducing proliferation, increasing apoptosis, and modifying the pattern of expression of adhesion molecules, especially those involved in plasma cell binding. These effects on BMSCs might explain the antitumor activity of ZOL.

Original languageEnglish
Pages (from-to)118-125
Number of pages8
JournalCancer
Volume104
Issue number1
DOIs
Publication statusPublished - Jul 1 2005

Fingerprint

zoledronic acid
Multiple Myeloma
Mesenchymal Stromal Cells
Down-Regulation
Apoptosis
Interleukin-6
DNA Nucleotidylexotransferase
Annexin A5
Plasma Cells
Fluorescein
Interleukin-1
Bone Marrow Cells

Keywords

  • Adhesion molecules
  • Antitumor effect
  • Apoptosis
  • Bone marrow stromal cells
  • Zoledronic acid

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Zoledronic acid down-regulates adhesion molecules of bone marrow stromal cells in multiple myeloma : A possible mechanism for its antitumor effect. / Corso, Alessandro; Ferretti, Eleonora; Lunghi, Monia; Zappasodi, Patrizia; Mangiacavalli, Silvia; De Amici, Mara; Rusconi, Chiara; Varettoni, Marzia; Lazzarino, Mario.

In: Cancer, Vol. 104, No. 1, 01.07.2005, p. 118-125.

Research output: Contribution to journalArticle

@article{5efac97130be4d4890a3d6247909c585,
title = "Zoledronic acid down-regulates adhesion molecules of bone marrow stromal cells in multiple myeloma: A possible mechanism for its antitumor effect",
abstract = "BACKGROUND. Myeloma plasma cells interact with the bone marrow microenvironment which, in turn, supports their growth and protects them from apoptosis. In vitro studies have demonstrated the antitumor potential of zoledronic acid (ZOL) on myeloma cell lines, but few data are available on its effects on bone marrow stromal cells (BMSCs). The aim of the current study was to evaluate the antiproliferative and apoptotic effect of ZOL on BMSCs, as well as its effect on the expression of adhesion molecules. METHODS. BMSCs, obtained from bone marrow mononucleated cells of 8 patients with multiple myeloma, were treated with increasing concentrations of ZOL for 3 days. Cytotoxic effect was analyzed by 3-(4-5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide; thiazolyl blue (MTT) assay whereas the induction of apoptosis was evaluated by flow cytometric detection of fluorescein isothiocyanate-labeled annexin V, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay, and nuclear changes. Moreover, expression of CD106, CD56, CD50, CD49d, CD44, and CD40 was analyzed by flow cytometry. Data were evaluated by the Friedman test. RESULTS. After 3 days of exposure at concentrations of 10-4 to 10-5 M, ZOL induced a decrease in proliferation (P <0.0001) and an increase in apoptosis (P <0.002). Analysis of culture supernatants showed that myeloma BMSCs expressed interleukin (IL)-6, negligible levels of tumor necrosis factor-alpha, and no IL-1β. In vitro exposure to the lowest concentrations of ZOL decreased IL-6 production by BMSCs. Among the adhesion molecules, CD106, CD54, CD49d, and CD40, which were strongly expressed at baseline, showed a statistically significant reduction compared with controls after exposure to ZOL. CONCLUSIONS. ZOL interfered with myeloma BMSCs by reducing proliferation, increasing apoptosis, and modifying the pattern of expression of adhesion molecules, especially those involved in plasma cell binding. These effects on BMSCs might explain the antitumor activity of ZOL.",
keywords = "Adhesion molecules, Antitumor effect, Apoptosis, Bone marrow stromal cells, Zoledronic acid",
author = "Alessandro Corso and Eleonora Ferretti and Monia Lunghi and Patrizia Zappasodi and Silvia Mangiacavalli and {De Amici}, Mara and Chiara Rusconi and Marzia Varettoni and Mario Lazzarino",
year = "2005",
month = "7",
day = "1",
doi = "10.1002/cncr.21104",
language = "English",
volume = "104",
pages = "118--125",
journal = "Cancer",
issn = "0008-543X",
publisher = "John Wiley and Sons Inc.",
number = "1",

}

TY - JOUR

T1 - Zoledronic acid down-regulates adhesion molecules of bone marrow stromal cells in multiple myeloma

T2 - A possible mechanism for its antitumor effect

AU - Corso, Alessandro

AU - Ferretti, Eleonora

AU - Lunghi, Monia

AU - Zappasodi, Patrizia

AU - Mangiacavalli, Silvia

AU - De Amici, Mara

AU - Rusconi, Chiara

AU - Varettoni, Marzia

AU - Lazzarino, Mario

PY - 2005/7/1

Y1 - 2005/7/1

N2 - BACKGROUND. Myeloma plasma cells interact with the bone marrow microenvironment which, in turn, supports their growth and protects them from apoptosis. In vitro studies have demonstrated the antitumor potential of zoledronic acid (ZOL) on myeloma cell lines, but few data are available on its effects on bone marrow stromal cells (BMSCs). The aim of the current study was to evaluate the antiproliferative and apoptotic effect of ZOL on BMSCs, as well as its effect on the expression of adhesion molecules. METHODS. BMSCs, obtained from bone marrow mononucleated cells of 8 patients with multiple myeloma, were treated with increasing concentrations of ZOL for 3 days. Cytotoxic effect was analyzed by 3-(4-5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide; thiazolyl blue (MTT) assay whereas the induction of apoptosis was evaluated by flow cytometric detection of fluorescein isothiocyanate-labeled annexin V, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay, and nuclear changes. Moreover, expression of CD106, CD56, CD50, CD49d, CD44, and CD40 was analyzed by flow cytometry. Data were evaluated by the Friedman test. RESULTS. After 3 days of exposure at concentrations of 10-4 to 10-5 M, ZOL induced a decrease in proliferation (P <0.0001) and an increase in apoptosis (P <0.002). Analysis of culture supernatants showed that myeloma BMSCs expressed interleukin (IL)-6, negligible levels of tumor necrosis factor-alpha, and no IL-1β. In vitro exposure to the lowest concentrations of ZOL decreased IL-6 production by BMSCs. Among the adhesion molecules, CD106, CD54, CD49d, and CD40, which were strongly expressed at baseline, showed a statistically significant reduction compared with controls after exposure to ZOL. CONCLUSIONS. ZOL interfered with myeloma BMSCs by reducing proliferation, increasing apoptosis, and modifying the pattern of expression of adhesion molecules, especially those involved in plasma cell binding. These effects on BMSCs might explain the antitumor activity of ZOL.

AB - BACKGROUND. Myeloma plasma cells interact with the bone marrow microenvironment which, in turn, supports their growth and protects them from apoptosis. In vitro studies have demonstrated the antitumor potential of zoledronic acid (ZOL) on myeloma cell lines, but few data are available on its effects on bone marrow stromal cells (BMSCs). The aim of the current study was to evaluate the antiproliferative and apoptotic effect of ZOL on BMSCs, as well as its effect on the expression of adhesion molecules. METHODS. BMSCs, obtained from bone marrow mononucleated cells of 8 patients with multiple myeloma, were treated with increasing concentrations of ZOL for 3 days. Cytotoxic effect was analyzed by 3-(4-5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide; thiazolyl blue (MTT) assay whereas the induction of apoptosis was evaluated by flow cytometric detection of fluorescein isothiocyanate-labeled annexin V, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay, and nuclear changes. Moreover, expression of CD106, CD56, CD50, CD49d, CD44, and CD40 was analyzed by flow cytometry. Data were evaluated by the Friedman test. RESULTS. After 3 days of exposure at concentrations of 10-4 to 10-5 M, ZOL induced a decrease in proliferation (P <0.0001) and an increase in apoptosis (P <0.002). Analysis of culture supernatants showed that myeloma BMSCs expressed interleukin (IL)-6, negligible levels of tumor necrosis factor-alpha, and no IL-1β. In vitro exposure to the lowest concentrations of ZOL decreased IL-6 production by BMSCs. Among the adhesion molecules, CD106, CD54, CD49d, and CD40, which were strongly expressed at baseline, showed a statistically significant reduction compared with controls after exposure to ZOL. CONCLUSIONS. ZOL interfered with myeloma BMSCs by reducing proliferation, increasing apoptosis, and modifying the pattern of expression of adhesion molecules, especially those involved in plasma cell binding. These effects on BMSCs might explain the antitumor activity of ZOL.

KW - Adhesion molecules

KW - Antitumor effect

KW - Apoptosis

KW - Bone marrow stromal cells

KW - Zoledronic acid

UR - http://www.scopus.com/inward/record.url?scp=20544473523&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=20544473523&partnerID=8YFLogxK

U2 - 10.1002/cncr.21104

DO - 10.1002/cncr.21104

M3 - Article

C2 - 15895374

AN - SCOPUS:20544473523

VL - 104

SP - 118

EP - 125

JO - Cancer

JF - Cancer

SN - 0008-543X

IS - 1

ER -