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Reduction of the putative CD44+CD24 breast cancer stem cell population by targeting the polyamine metabolic pathway with PG11047

Cirenajwis, Helenaa; Smiljanic, Sandraa; Honeth, Gabriellab; Hegardt, Ceciliab; Marton, Laurence J.c; Oredsson, Stina M.a

doi: 10.1097/CAD.0b013e32833f2f77
Preclinical Reports

Cancer stem cells (CSCs) are considered to be of particular concern in cancer as they possess inherent properties of self-renewal and differentiation, along with expressing certain genes related to a mesenchymal phenotype. These features favour the promotion of tumour recurrence and metastasis in cancer patients. Thus, the optimal chemotherapeutic treatment should target the CSC population, either by killing these cells and/or by inducing their transition to a more differentiated epithelial-like phenotype. Experiments were carried out on the trastuzumab-resistant human epidermal growth factor receptor 2-overexpressing breast cancer cell line JIMT-1 to unravel the chemotherapeutic effects of the polyamine analogue [1N,12N]bis(ethyl)-cis-6,7-dehydrospermine (PG11047) and of the polyamine biosynthetic inhibitor 2-difluoromethylornithine (DFMO) on the CD44+CD24 CSC population. Furthermore, effects on the properties of self-renewal and epithelial/mesenchymal markers were also investigated. Treatment with PG11047 reduced the CD44+CD24 subpopulation of JIMT-1 cells by approximately 50%, inhibited and/or reduced self-renewal capability of the CSC population, decreased cell motility and induced expression of mesenchymal to epithelial transition-associated proteins that are involved in promoting an epithelial phenotype. By contrast, DFMO slightly increased the CD44+CD24 subpopulation, increased cell motility and the level of mesenchymal-related proteins. DFMO treatment reduced the self-renewal capability of the CSC population. Both PG11047 and DFMO reduced the expression of the human epidermal growth factor receptor 2 protein, which is correlated to malignancy and resistance to trastuzumab in JIMT-1 cells. Our findings indicate that treatment with PG11047 targeted the CSC population by interfering with several stem cell-related properties, such as self-renewal, differentiation, motility and the mesenchymal phenotype.

aDepartment of Biology, Division of Cell and Organism Biology

bDepartment of Oncology, Clinical Sciences, Lund University, Lund, Sweden

cProgen Pharmaceuticals, Palo Alto, California, USA

Correspondence to Helena Cirenajwis, Institution of Biology, Sölvegatan 35A, SE-223 62 Lund, Sweden

Tel: +4646 2224587; fax: +4646 2224425;

e-mail: helena.cirenajwis@cob.lu.se

Received 9 July 2010 Revised form accepted 9 August 2010

© 2010 Lippincott Williams & Wilkins, Inc.