Khadijeh Moradi, Farnaz Barneh, Saeed Irian, Mohsen Amini, Raheleh Moradpoor, Amir Amanzadeh, Samira Choopani, Hamzeh Rahimi, Tayebeh Ghodselahi, Massoud M. Boujar and Mona Salimi* Pages 1002 - 1011 ( 10 )
Background: The concept of Epithelial-Mesenchymal Transition (EMT) to promote carcinoma progression has been recognized as a venue for research on novel anticancer drugs. Triaryl template-based structures are one of the pivotal structural features found in a number of compounds with a wide variety of biological properties including anti-breast cancer. Among the various factors triggering EMT program, cyclooxygenase-2 (COX-2), NF-κB as well as the transforming growth factor-beta (TGF-β) have been widely investigated.
Objective: Here, we aim to investigate the effect of two novel compounds A and B possessing triaryl structures, which interact with both COX-2 and TGF-β active sites and suppress NF-κB activation, on EMT in a co-culture system with breast cancer and stromal cells.
Methods: MDA-MB-231 and bone-marrow mesenchymal stem (BM-MS) cells were co-cultured in a trans-well plate. Migration, matrigel-based invasion and colony formation in soft agar assays along with Real- time PCR and Western blot analysis were performed to examine the effect of compounds A and B on the invasive properties of MDA-MB-231 cells after 72 hours of co-culturing with BM-MSCs. In addition, TGF-beta interaction was investigated by Localized Surface Plasmon Resonance (LSPR).
Results: BM-MSCs enhanced migration, invasion and anchorage-independent growth of the co-cultured MDAMB- 231 cells. A reduction in E-cadherin level concomitant with an increase in vimentin and N-cadherin levels following the co-culture implied EMT as the underlying process. Compounds A and B inhibited invasion and anchorage-independent growth of breast cancer cells co-cultured with BM-MSCs at 10µM. The observed inhibitory effects along with an increase in E-cadherin and a reduction in vimentin and ZEB2 levels suggest that the anti-invasive properties of compounds A and B might proceed through the blockade of stromal cell-induced EMT, mediated by their interaction with TGF-beta.
Conclusion: These findings introduce compounds A and B as novel promising agents, which prevent EMT in invasive breast cancer cells.
Breast cancer, metastasis, EMT, bone marrow mesenchymal stem cells, triaryl, localized surface plasmon resonance.
Department of Cell and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Department of Basic Sciences, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Department of Cell and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Medicinal Chemistry Department, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Department of Basic Sciences, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, National Cell Bank of Iran, Pasteur Institute of Iran, Tehran, Physiology and Pharmacology Department, Pasteur Institute of Iran, Tehran, Molecular Medicine Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Nano Mabna Iranian Inc. P.O. Box 1676664116, Tehran, Department of Cell and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Physiology and Pharmacology Department, Pasteur Institute of Iran, Tehran