Two Novel Tri-Aryl Derivatives Attenuate the Invasion-Promoting Effects of Stromal Mesenchymal Stem Cells on Breast Cancer

Author(s): Khadijeh Moradi, Farnaz Barneh, Saeed Irian, Mohsen Amini, Raheleh Moradpoor, Amir Amanzadeh, Samira Choopani, Hamzeh Rahimi, Tayebeh Ghodselahi, Massoud M. Boujar, Mona Salimi*.

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 19 , Issue 8 , 2019

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Graphical Abstract:


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.

Keywords: Breast cancer, metastasis, EMT, bone marrow mesenchymal stem cells, triaryl, localized surface plasmon resonance.

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Article Details

VOLUME: 19
ISSUE: 8
Year: 2019
Page: [1002 - 1011]
Pages: 10
DOI: 10.2174/1871520619666190212123912
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