Innovative thiosemicarbazones that induce multi-modal mechanisms to down-regulate estrogen-, progesterone-, androgen- and prolactin-receptors in breast cancer

• Published in: Pharmacological research Vol. 193; p. 106806
• Main Authors: Shehadeh-Tout, Faten, Milioli, Heloisa H., Roslan, Suraya, Jansson, Patric J., Dharmasivam, Mahendiran, Graham, Dinny, Anderson, Robin, Wijesinghe, Tharushi, Azad, Mahan Gholam, Richardson, Des R., Kovacevic, Zaklina
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01-07-2023; Elsevier
• Subjects: Estrogen receptor; Molecular pharmacology; Tamoxifen; Thiosemicarbazones; BC; Estrogen receptor; PRL-R; JNK; RTK; SRC3; DFO; E2; NDRG1; EGFR; DMEM; NF-κB; PI3K; DpC; TGF-α; IGF-1R; Molecular pharmacology; Bp2mT; MAPK; Tamoxifen; ER; 4-OHT; AR; Thiosemicarbazones; ERE; HER2; RPMI; Dp44mT; HER3
• ISSN: 1043-6618; 1096-1186
• DOI: 10.1016/j.phrs.2023.106806

The estrogen receptor-α (ER-α) is a key driver of breast cancer (BC) and the ER-antagonist, tamoxifen, is a central pillar of BC treatment. However, cross-talk between ER-α, other hormone and growth factor receptors enables development of de novo resistance to tamoxifen. Herein, we mechanistically dissect the activity of a new class of anti-cancer agents that inhibit multiple growth factor receptors and down-stream signaling for the treatment of ER-positive BC. Using RNA sequencing and comprehensive protein expression analysis, we examined the activity of di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), on the expression and activation of hormone and growth factor receptors, co-factors, and key resistance pathways in ER-α-positive BC. DpC differentially regulated 106 estrogen-response genes, and this was linked to decreased mRNA levels of 4 central hormone receptors involved in BC pathogenesis, namely ER, progesterone receptor (PR), androgen receptor (AR), and prolactin receptor (PRL-R). Mechanistic investigation demonstrated that due to DpC and Dp44mT binding metal ions, these agents caused a pronounced decrease in ER-α, AR, PR, and PRL-R protein expression. DpC and Dp44mT also inhibited activation and down-stream signaling of the epidermal growth factor (EGF) family receptors, and expression of co-factors that promote ER-α transcriptional activity, including SRC3, NF-κB p65, and SP1. In vivo, DpC was highly tolerable and effectively inhibited ER-α-positive BC growth. Through bespoke, non-hormonal, multi-modal mechanisms, Dp44mT and DpC decrease the expression of PR, AR, PRL-R, and tyrosine kinases that act with ER-α to promote BC, constituting an innovative therapeutic approach.
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