Contact
    Start Publications Biomimetic sulfated glycosaminoglycans maintain differentiation ...
    ←  Publication Finder
    QSense

    Biomimetic sulfated glycosaminoglycans maintain differentiation markers of breast epithelial cells and preferentially inhibit proliferation of cancer cells

    Year: 2021

    Journal: Acta Biomater., Volume 122, MAR 1, page 186–198

    Authors: Habli, Zeina; Al Deen, Nataly Naser; Malaeb, Waddah; Mahfouz, Nadine; Mermerian, Angela; Talhouk, Rabih; Mhanna, Rami

    Organizations: American University of Beirut Collaborative Research Stimulus (CRS) grant; Lebanese National Council for Scientific Research (CNRS-L); AUB-CNRS-L Scholarship

    Keywords: Glycosaminoglycans; Sulfated alginates; Biomimetics; Breast cancer; Therapeutics

    Glycosaminoglycans (GAG) are key elements involved in various physiological and pathological processes including cancer. Several GAG-based drugs have been developed showing significant results and potential use as cancer therapeutics. We previously reported that alginate sulfate (AlgSulf), a GAG-mimetic, reduces the proliferation of lung adenocarcinoma cells. In this study, we evaluated the preferential effect of AlgSulf on tumorigenic and nontumorigenic mammary epithelial cells in 2D, 3D, and coculture conditions. AlgSulf were synthesized with different degrees of sulfation (DSs) varying from 0 to 2.7 and used at 100 mu g/mL on HMT-3522 S1 (S1) nontumorigenic mammary epithelial cells and their tumorigenic counterparts HMT-3522 T4-2 (T4-2) cells. The anti-tumor properties of AlgSulf were assessed using trypan blue and bromodeoxyuridine proliferation (BrdU) assays, immunofluorescence staining and transwell invasion assay. Binding of insulin and epidermal growth factor (EGF) to sulfated substrates was measured using QCM-D and ELISA. In 2D, the cell growth rate of cells treated with AlgSulf was consistently lower compared to untreated controls (p < 0.001) and surpassed the effect of the native GAG heparin (positive control). In 3D, AlgSulf preferentially hindered the growth rate and the invasion potential of tumorigenic T4-2 nodules while maintaining the formation of differentiated polarized nontumorigenic S1 acini. The preferential growth inhibition of tumorigenic cells by AlgSulf was confirmed in a coculture system (p < 0.001). In the ELISA assay, a trend of EGF binding was detected for sulfated polysaccharides while QCM-D analysis showed negligible binding of insulin and EGF to sulfated substrates. The preferential effect mediated by the mimetic sulfated GAGs on cancer cells may in part be growth factor dependent. Our findings suggest a potential anticancer therapeutic role of AlgSulf for the development of anticancer drugs. Statement of significance Sulfated glycosaminoglycans (GAGs) of the extracellular matrix such as heparin interact with growth factors and growth factor receptors leading to profound effects on cellular processes including tumor growth and tumor inhibition. GAGs sulfation patterns have been shown to modulate their function through unclear mechanisms of action. Understanding the structure/activity relation in sulfated GAGs has led to the development of novel drugs for cancer treatment. Alginate sulfates (AlgSulf) are polysaccharides with defined homogenous sulfation codes mimicking native sulfated GAGs. Herein, we report a robust preferential inhibitory effect of the heparin-mimetic AlgSulf against breast cancer cells using a unique model of cell culture. Surprisingly, AlgSulf selectively targets cancer cells, rendering normal cells unaffected. Our findings suggest that AlgSulf represent a promising new class of anticancer biomimetic GAGs. (C) 2021 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
    View publication