A combination treatment with DNA methyltransferase inhibitors and suramin decreases invasiveness of breast cancer cells

Sahra Borges, Heike R. Döppler, Peter Storz

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

The treatment of patients with invasive breast cancer remains a major issue because of the acquisition of drug resistance to conventional chemotherapy. Here we propose a new therapeutic strategy by combining DNA methyltransferase inhibitors (DMTIs) with suramin. Cytotoxic effects of suramin or combination treatment with DMTIs were determined in highly invasive breast cancer cell lines MDA-MB-231, BT-20 and HCC1954, or control cells. In addition, effects on cell invasion were determined in 3-dimensional cell culture assays. DMTI-mediated upregulation of Protein Kinase D1 (PKD1) expression was shown by Western blotting. Effects of suramin on PKD1 activity was determined in vitro and in cells. The importance of PKD1 in mediating the effects of such combination treatment in cell invasion was demonstrated using 3D cell culture assays. A proof of principal animal experiment was performed showing that PKD1 is critical for breast cancer growth. We show that when used in combination, suramin and DMTIs impair the invasive phenotype of breast cancer cells. We show that PKD1, a kinase that previously has been described as a suppressor of tumor cell invasion, is an interface for both FDA-approved drugs, since the additive effects observed are due to DMTI-mediated re-expression and suramin-induced activation of PKD1. Our data reveal a mechanism of how a combination treatment with non-toxic doses of suramin and DMTIs may be of therapeutic benefit for patients with aggressive, multi-drug resistant breast cancer.

Original languageEnglish (US)
Pages (from-to)79-91
Number of pages13
JournalBreast Cancer Research and Treatment
Volume144
Issue number1
DOIs
StatePublished - 2014

Fingerprint

Suramin
Methyltransferases
Protein Kinases
Breast Neoplasms
DNA
Therapeutics
Cell Culture Techniques
Drug Resistance
Pharmaceutical Preparations
Phosphotransferases
Up-Regulation
Western Blotting
Phenotype
Drug Therapy
Cell Line
Growth
Neoplasms

Keywords

  • Breast cancer
  • Invasive phenotype
  • MDA-MB-231
  • Methyltransferase inhibitors
  • Suramin

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

A combination treatment with DNA methyltransferase inhibitors and suramin decreases invasiveness of breast cancer cells. / Borges, Sahra; Döppler, Heike R.; Storz, Peter.

In: Breast Cancer Research and Treatment, Vol. 144, No. 1, 2014, p. 79-91.

Research output: Contribution to journalArticle

@article{d391849a09f94e25b295a32ba867f6c3,
title = "A combination treatment with DNA methyltransferase inhibitors and suramin decreases invasiveness of breast cancer cells",
abstract = "The treatment of patients with invasive breast cancer remains a major issue because of the acquisition of drug resistance to conventional chemotherapy. Here we propose a new therapeutic strategy by combining DNA methyltransferase inhibitors (DMTIs) with suramin. Cytotoxic effects of suramin or combination treatment with DMTIs were determined in highly invasive breast cancer cell lines MDA-MB-231, BT-20 and HCC1954, or control cells. In addition, effects on cell invasion were determined in 3-dimensional cell culture assays. DMTI-mediated upregulation of Protein Kinase D1 (PKD1) expression was shown by Western blotting. Effects of suramin on PKD1 activity was determined in vitro and in cells. The importance of PKD1 in mediating the effects of such combination treatment in cell invasion was demonstrated using 3D cell culture assays. A proof of principal animal experiment was performed showing that PKD1 is critical for breast cancer growth. We show that when used in combination, suramin and DMTIs impair the invasive phenotype of breast cancer cells. We show that PKD1, a kinase that previously has been described as a suppressor of tumor cell invasion, is an interface for both FDA-approved drugs, since the additive effects observed are due to DMTI-mediated re-expression and suramin-induced activation of PKD1. Our data reveal a mechanism of how a combination treatment with non-toxic doses of suramin and DMTIs may be of therapeutic benefit for patients with aggressive, multi-drug resistant breast cancer.",
keywords = "Breast cancer, Invasive phenotype, MDA-MB-231, Methyltransferase inhibitors, Suramin",
author = "Sahra Borges and D{\"o}ppler, {Heike R.} and Peter Storz",
year = "2014",
doi = "10.1007/s10549-014-2857-2",
language = "English (US)",
volume = "144",
pages = "79--91",
journal = "Breast Cancer Research and Treatment",
issn = "0167-6806",
publisher = "Springer New York",
number = "1",

}

TY - JOUR

T1 - A combination treatment with DNA methyltransferase inhibitors and suramin decreases invasiveness of breast cancer cells

AU - Borges, Sahra

AU - Döppler, Heike R.

AU - Storz, Peter

PY - 2014

Y1 - 2014

N2 - The treatment of patients with invasive breast cancer remains a major issue because of the acquisition of drug resistance to conventional chemotherapy. Here we propose a new therapeutic strategy by combining DNA methyltransferase inhibitors (DMTIs) with suramin. Cytotoxic effects of suramin or combination treatment with DMTIs were determined in highly invasive breast cancer cell lines MDA-MB-231, BT-20 and HCC1954, or control cells. In addition, effects on cell invasion were determined in 3-dimensional cell culture assays. DMTI-mediated upregulation of Protein Kinase D1 (PKD1) expression was shown by Western blotting. Effects of suramin on PKD1 activity was determined in vitro and in cells. The importance of PKD1 in mediating the effects of such combination treatment in cell invasion was demonstrated using 3D cell culture assays. A proof of principal animal experiment was performed showing that PKD1 is critical for breast cancer growth. We show that when used in combination, suramin and DMTIs impair the invasive phenotype of breast cancer cells. We show that PKD1, a kinase that previously has been described as a suppressor of tumor cell invasion, is an interface for both FDA-approved drugs, since the additive effects observed are due to DMTI-mediated re-expression and suramin-induced activation of PKD1. Our data reveal a mechanism of how a combination treatment with non-toxic doses of suramin and DMTIs may be of therapeutic benefit for patients with aggressive, multi-drug resistant breast cancer.

AB - The treatment of patients with invasive breast cancer remains a major issue because of the acquisition of drug resistance to conventional chemotherapy. Here we propose a new therapeutic strategy by combining DNA methyltransferase inhibitors (DMTIs) with suramin. Cytotoxic effects of suramin or combination treatment with DMTIs were determined in highly invasive breast cancer cell lines MDA-MB-231, BT-20 and HCC1954, or control cells. In addition, effects on cell invasion were determined in 3-dimensional cell culture assays. DMTI-mediated upregulation of Protein Kinase D1 (PKD1) expression was shown by Western blotting. Effects of suramin on PKD1 activity was determined in vitro and in cells. The importance of PKD1 in mediating the effects of such combination treatment in cell invasion was demonstrated using 3D cell culture assays. A proof of principal animal experiment was performed showing that PKD1 is critical for breast cancer growth. We show that when used in combination, suramin and DMTIs impair the invasive phenotype of breast cancer cells. We show that PKD1, a kinase that previously has been described as a suppressor of tumor cell invasion, is an interface for both FDA-approved drugs, since the additive effects observed are due to DMTI-mediated re-expression and suramin-induced activation of PKD1. Our data reveal a mechanism of how a combination treatment with non-toxic doses of suramin and DMTIs may be of therapeutic benefit for patients with aggressive, multi-drug resistant breast cancer.

KW - Breast cancer

KW - Invasive phenotype

KW - MDA-MB-231

KW - Methyltransferase inhibitors

KW - Suramin

UR - http://www.scopus.com/inward/record.url?scp=84896714346&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84896714346&partnerID=8YFLogxK

U2 - 10.1007/s10549-014-2857-2

DO - 10.1007/s10549-014-2857-2

M3 - Article

C2 - 24510012

AN - SCOPUS:84896714346

VL - 144

SP - 79

EP - 91

JO - Breast Cancer Research and Treatment

JF - Breast Cancer Research and Treatment

SN - 0167-6806

IS - 1

ER -