Abstract
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.
Original language | English |
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Pages (from-to) | 1002-1011 |
Number of pages | 10 |
Journal | Anti-Cancer Agents in Medicinal Chemistry |
Volume | 19 |
Issue number | 8 |
DOIs | |
Publication status | Published - 2019 |
Externally published | Yes |
Keywords
- Bone marrow mesenchymal stem cells
- Breast cancer
- EMT
- Localized surface plasmon resonance
- Metastasis
- Triaryl