Innovative thiosemicarbazones that induce multi-modal mechanisms to down-regulate estrogen-, progesterone-, androgen- and prolactin-receptors in breast cancer
Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:193 |
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| Enthalten in: |
Pharmacological research - 193(2023) vom: 15. Juli, Seite 106806 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Shehadeh-Tout, Faten [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 23.06.2023 Date Revised 25.06.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.phrs.2023.106806 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Estrogen receptor | |
| 650 | 4 | |a Molecular pharmacology | |
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| 700 | 1 | |a Milioli, Heloisa H |e verfasserin |4 aut | |
| 700 | 1 | |a Roslan, Suraya |e verfasserin |4 aut | |
| 700 | 1 | |a Jansson, Patric J |e verfasserin |4 aut | |
| 700 | 1 | |a Dharmasivam, Mahendiran |e verfasserin |4 aut | |
| 700 | 1 | |a Graham, Dinny |e verfasserin |4 aut | |
| 700 | 1 | |a Anderson, Robin |e verfasserin |4 aut | |
| 700 | 1 | |a Wijesinghe, Tharushi |e verfasserin |4 aut | |
| 700 | 1 | |a Azad, Mahan Gholam |e verfasserin |4 aut | |
| 700 | 1 | |a Richardson, Des R |e verfasserin |4 aut | |
| 700 | 1 | |a Kovacevic, Zaklina |e verfasserin |4 aut | |
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