Acquisition of resistance toward HYD1 correlates with a reduction in cleaved α4 integrin expression and a compromised CAM-DR phenotype

Michael F. Emmons, Anthony W. Gebhard, Rajesh R. Nair, Rachid Baz, Mark L. McLaughlin, Anne E Cress, Lori A. Hazlehurst

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

We recently reported that the β1 integrin antagonist, referred to as HYD1, induces necrotic cell death in myeloma cell lines as a single agent using in vitro and in vivo models. In this article, we sought to delineate the determinants of sensitivity and resistance toward HYD1-induced cell death. To this end, we developed an HYD1 isogenic resistant myeloma cell line by chronically exposing H929 myeloma cells to increasing concentrations of HYD1. Our data indicate that the acquisition of resistance toward HYD1 correlates with reduced levels of the cleaved α4 integrin subunit. Consistent with reduced VLA-4 (α4β1) expression, the resistant variant showed ablated functional binding to fibronectin, VCAM-1, and the bone marrow stroma cell line HS-5. The reduction in binding of the resistant cell line to HS-5 cells translated to a compromised cell adhesion-mediated drug resistant phenotype as shown by increased sensitivity to melphalan- and bortezomib-induced cell death in the bone marrow stroma coculture model of drug resistance. Importantly, we show that HYD1 is more potent in relapsed myeloma specimens than newly diagnosed patients, a finding that correlated with α4 integrin expression. Collectively, these data indicate that this novel D-amino acid peptide may represent a good candidate for pursuing clinical trials in relapsed myeloma and in particular patients with high levels of α4 integrin. Moreover, our data provide further rationale for continued preclinical development of HYD1 and analogues of HYD1 for the treatment of multiple myeloma and potentially other tumors that home and/or metastasize to the bone.

Original languageEnglish (US)
Pages (from-to)2257-2266
Number of pages10
JournalMolecular Cancer Therapeutics
Volume10
Issue number12
DOIs
StatePublished - Dec 2011

Fingerprint

Integrins
Phenotype
Cell Line
Cell Death
Integrin alpha4beta1
Melphalan
Vascular Cell Adhesion Molecule-1
Coculture Techniques
Multiple Myeloma
Fibronectins
Drug Resistance
Cell Adhesion
Bone Marrow Cells
Bone Marrow
Clinical Trials
Amino Acids
Bone and Bones
Peptides
Pharmaceutical Preparations
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Acquisition of resistance toward HYD1 correlates with a reduction in cleaved α4 integrin expression and a compromised CAM-DR phenotype. / Emmons, Michael F.; Gebhard, Anthony W.; Nair, Rajesh R.; Baz, Rachid; McLaughlin, Mark L.; Cress, Anne E; Hazlehurst, Lori A.

In: Molecular Cancer Therapeutics, Vol. 10, No. 12, 12.2011, p. 2257-2266.

Research output: Contribution to journalArticle

Emmons, Michael F. ; Gebhard, Anthony W. ; Nair, Rajesh R. ; Baz, Rachid ; McLaughlin, Mark L. ; Cress, Anne E ; Hazlehurst, Lori A. / Acquisition of resistance toward HYD1 correlates with a reduction in cleaved α4 integrin expression and a compromised CAM-DR phenotype. In: Molecular Cancer Therapeutics. 2011 ; Vol. 10, No. 12. pp. 2257-2266.
@article{e1f9f88909bd4f2dad10ece4684a3232,
title = "Acquisition of resistance toward HYD1 correlates with a reduction in cleaved α4 integrin expression and a compromised CAM-DR phenotype",
abstract = "We recently reported that the β1 integrin antagonist, referred to as HYD1, induces necrotic cell death in myeloma cell lines as a single agent using in vitro and in vivo models. In this article, we sought to delineate the determinants of sensitivity and resistance toward HYD1-induced cell death. To this end, we developed an HYD1 isogenic resistant myeloma cell line by chronically exposing H929 myeloma cells to increasing concentrations of HYD1. Our data indicate that the acquisition of resistance toward HYD1 correlates with reduced levels of the cleaved α4 integrin subunit. Consistent with reduced VLA-4 (α4β1) expression, the resistant variant showed ablated functional binding to fibronectin, VCAM-1, and the bone marrow stroma cell line HS-5. The reduction in binding of the resistant cell line to HS-5 cells translated to a compromised cell adhesion-mediated drug resistant phenotype as shown by increased sensitivity to melphalan- and bortezomib-induced cell death in the bone marrow stroma coculture model of drug resistance. Importantly, we show that HYD1 is more potent in relapsed myeloma specimens than newly diagnosed patients, a finding that correlated with α4 integrin expression. Collectively, these data indicate that this novel D-amino acid peptide may represent a good candidate for pursuing clinical trials in relapsed myeloma and in particular patients with high levels of α4 integrin. Moreover, our data provide further rationale for continued preclinical development of HYD1 and analogues of HYD1 for the treatment of multiple myeloma and potentially other tumors that home and/or metastasize to the bone.",
author = "Emmons, {Michael F.} and Gebhard, {Anthony W.} and Nair, {Rajesh R.} and Rachid Baz and McLaughlin, {Mark L.} and Cress, {Anne E} and Hazlehurst, {Lori A.}",
year = "2011",
month = "12",
doi = "10.1158/1535-7163.MCT-11-0149",
language = "English (US)",
volume = "10",
pages = "2257--2266",
journal = "Molecular Cancer Therapeutics",
issn = "1535-7163",
publisher = "American Association for Cancer Research Inc.",
number = "12",

}

TY - JOUR

T1 - Acquisition of resistance toward HYD1 correlates with a reduction in cleaved α4 integrin expression and a compromised CAM-DR phenotype

AU - Emmons, Michael F.

AU - Gebhard, Anthony W.

AU - Nair, Rajesh R.

AU - Baz, Rachid

AU - McLaughlin, Mark L.

AU - Cress, Anne E

AU - Hazlehurst, Lori A.

PY - 2011/12

Y1 - 2011/12

N2 - We recently reported that the β1 integrin antagonist, referred to as HYD1, induces necrotic cell death in myeloma cell lines as a single agent using in vitro and in vivo models. In this article, we sought to delineate the determinants of sensitivity and resistance toward HYD1-induced cell death. To this end, we developed an HYD1 isogenic resistant myeloma cell line by chronically exposing H929 myeloma cells to increasing concentrations of HYD1. Our data indicate that the acquisition of resistance toward HYD1 correlates with reduced levels of the cleaved α4 integrin subunit. Consistent with reduced VLA-4 (α4β1) expression, the resistant variant showed ablated functional binding to fibronectin, VCAM-1, and the bone marrow stroma cell line HS-5. The reduction in binding of the resistant cell line to HS-5 cells translated to a compromised cell adhesion-mediated drug resistant phenotype as shown by increased sensitivity to melphalan- and bortezomib-induced cell death in the bone marrow stroma coculture model of drug resistance. Importantly, we show that HYD1 is more potent in relapsed myeloma specimens than newly diagnosed patients, a finding that correlated with α4 integrin expression. Collectively, these data indicate that this novel D-amino acid peptide may represent a good candidate for pursuing clinical trials in relapsed myeloma and in particular patients with high levels of α4 integrin. Moreover, our data provide further rationale for continued preclinical development of HYD1 and analogues of HYD1 for the treatment of multiple myeloma and potentially other tumors that home and/or metastasize to the bone.

AB - We recently reported that the β1 integrin antagonist, referred to as HYD1, induces necrotic cell death in myeloma cell lines as a single agent using in vitro and in vivo models. In this article, we sought to delineate the determinants of sensitivity and resistance toward HYD1-induced cell death. To this end, we developed an HYD1 isogenic resistant myeloma cell line by chronically exposing H929 myeloma cells to increasing concentrations of HYD1. Our data indicate that the acquisition of resistance toward HYD1 correlates with reduced levels of the cleaved α4 integrin subunit. Consistent with reduced VLA-4 (α4β1) expression, the resistant variant showed ablated functional binding to fibronectin, VCAM-1, and the bone marrow stroma cell line HS-5. The reduction in binding of the resistant cell line to HS-5 cells translated to a compromised cell adhesion-mediated drug resistant phenotype as shown by increased sensitivity to melphalan- and bortezomib-induced cell death in the bone marrow stroma coculture model of drug resistance. Importantly, we show that HYD1 is more potent in relapsed myeloma specimens than newly diagnosed patients, a finding that correlated with α4 integrin expression. Collectively, these data indicate that this novel D-amino acid peptide may represent a good candidate for pursuing clinical trials in relapsed myeloma and in particular patients with high levels of α4 integrin. Moreover, our data provide further rationale for continued preclinical development of HYD1 and analogues of HYD1 for the treatment of multiple myeloma and potentially other tumors that home and/or metastasize to the bone.

UR - http://www.scopus.com/inward/record.url?scp=83355163335&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=83355163335&partnerID=8YFLogxK

U2 - 10.1158/1535-7163.MCT-11-0149

DO - 10.1158/1535-7163.MCT-11-0149

M3 - Article

C2 - 21980133

AN - SCOPUS:83355163335

VL - 10

SP - 2257

EP - 2266

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

SN - 1535-7163

IS - 12

ER -