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Published on: June 6, 2016
Two Novel Tri-Aryl Derivatives Attenuate the Invasion-Promoting Effects of Stromal Mesenchymal Stem Cells on Breast
Khadijeh Moradi1,2, Farnaz Barneh2,3, Saeed Irian1
1Department of Cell and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran.
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.
Insights
Two novel triaryl compounds inhibit cancer cell invasion by blocking cancer-associated fibroblast-induced Epithelial-Mesenchymal Transition (EMT). These compounds show promise as new anticancer drugs by targeting transforming growth factor-beta (TGF-β) signaling.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Epithelial-Mesenchymal Transition (EMT) promotes carcinoma progression and is a target for novel anticancer drugs.
- Triaryl structures are found in compounds with anti-breast cancer properties.
- Cyclooxygenase-2 (COX-2), NF-κB, and transforming growth factor-beta (TGF-β) are key factors in EMT.
Purpose of the Study:
- To investigate the effect of two novel triaryl compounds (A and B) on EMT in a co-culture system of breast cancer and stromal cells.
- To determine if compounds A and B suppress NF-κB activation and interact with COX-2 and TGF-β active sites.
- To evaluate the anti-invasive properties of compounds A and B against breast cancer cells.
Main Methods:
- Co-culture of MDA-MB-231 breast cancer cells and bone-marrow mesenchymal stem cells (BM-MSCs).
- Assays for cell migration, invasion, and anchorage-independent growth.
- Real-time PCR, Western blot, and Localized Surface Plasmon Resonance (LSPR) for molecular analysis and TGF-β interaction.
Main Results:
- BM-MSCs enhanced MDA-MB-231 cell migration, invasion, and growth, indicating EMT.
- Compounds A and B (at 10µM) inhibited invasion and growth, increasing E-cadherin and decreasing vimentin and ZEB2 levels.
- Inhibition of EMT and anti-invasive effects are likely mediated by TGF-β interaction.
Conclusions:
- Compounds A and B effectively inhibit stromal cell-induced EMT in invasive breast cancer.
- These novel triaryl compounds demonstrate potential as therapeutic agents against invasive breast cancer by blocking EMT.
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