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.
authors: Department of Cancer Biology, Mayo Clinic, Griffin Building, Room 306, 4,500 San Pablo Road, Jacksonville, FL, 32224, USA.
authors: Sahra
authors: S
authors: Borges
authors: Heike R
authors: HR
authors: Döppler
authors: Peter
authors: P
authors: Storz
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects*; D000077209:Decitabine; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology; D010797:Phthalimides / Q000008:administration & dosage; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013498:Suramin / Q000008:administration & dosage; D014364:Tryptophan / Q000008:administration & dosage / Q000031:analogs & derivatives; D023041:Xenograft Model Antitumor Assays
chemical_list: D004791:Enzyme Inhibitors; D010797:Phthalimides; C503639:RG108; D013498:Suramin; D000077209:Decitabine; D014364:Tryptophan; D001374:Azacitidine