A novel chalcone-based molecule, BDP inhibits MDA-MB-231 triple-negative breast cancer cell growth by suppressing Hsp90 function

Abstract

Triple-negative breast cancer (TNBC) is a molecularly diverse and heterogeneous disease and the molecular heterogeneity of TNBC increases the difficulty in improving survival rates. To date, therapeutic approaches for the treatment of TNBC such as hormonal chemotherapy and trastuzumab-based therapy have been limited by the lack of target receptors such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (Her2), emphasizing the urgent need for identifying new therapeutic options. In this regard, heat shock protein 90 (Hsp90) has emerged as an attractive therapeutic target for TNBC. Hsp90 plays a central role in regulating correct folding, stability, and function of numerous oncogenic proteins. In the present study, we evaluated the in vitro effect of a small molecule Hsp90 inhibitor, (E)-3-(2-bromo-3,4,5-trimethoxyphenyl)-1-(2,4-dihydroxyphenyl)prop-2-en-1-one (BDP) on TNBC cell line, MDA‑MB‑231. This study indicated that BDP efficiently inhibited the growth of MDA‑MB‑231 cells in a dose- and time-dependent manner. BDP induced overall degradation of multiple oncogenic proteins including EGFR, Her2, Met, Akt, c‑Raf, and Cdk4, consequently leading to apoptotic cell death. The flow cytometric analysis revealed that BDP promoted cell cycle arrest at G2/M phases. Moreover, BDP treatment attenuated the migration of MDA‑MB‑231 cells and impaired MMP9 activity, which are essential processes for tumor metastasis. Collectively, BDP represents a new class of Hsp90 inhibitor and shows therapeutic potential for TNBC treatment.

Chalcone Derivatives: Role in Anticancer Therapy

“…These drugs represent a promising strategy for developing chalcones as novel anticancer agents. Recently, Jeong et al [ 218 ] and Oh et al [ 219 ] have shown that synthetic chalcones can have a heat-shock protein 90 (HSP90)-induced inhibitory effect, which opens new perspectives into cancer treatment through the destabilization proteins by which cancer cells survive and multiply (tumorigenesis) [ 220 ]. Several phase II clinical trials of new anticancer molecules that have two hydroxyl groups at positions 1 and 3 have revealed the inhibition of interactions between HSP90 and patient proteins through the binding of these molecules to the ATP site in HSP90 [ 221 , 222 ].…”

Novel dual inhibitor for targeting PIM1 and FGFR1 kinases inhibits colorectal cancer growth in vitro and patient-derived xenografts in vivo

“…Chalcone inhibits the growth of breast cancer cells by regulating the cell cycle and apoptosis 54 . A previous study discovered novel chalcone derivatives as potential inhibitors of epidermal growth factor receptor (EGFR) for treatment of bladder cancer 55 .…”

Novel Insights into the Mode of Action of Vasorelaxant Synthetic Polyoxygenated Chalcones

“…ERα has already been identified as a target for chalcones, especially in the field of cancer [17,33] and it is now well accepted that estrogens can protect against cardiovascular diseases [11,34,35]. At the vascular level, ERα pathway can, through a non-genomic mechanism, lead to an endothelium-dependent vasodilation [34,36].…”