Please use this identifier to cite or link to this item:
Title: Innovative thiosemicarbazones that induce multi-modal mechanisms to down-regulate estrogen-, progesterone-, androgen- and prolactin-receptors in breast cancer.
Austin Authors: Shehadeh-Tout, Faten;Milioli, Heloisa H;Roslan, Suraya;Jansson, Patric J;Dharmasivam, Mahendiran;Graham, Dinny;Anderson, Robin L ;Wijesinghe, Tharushi;Azad, Mahan Gholam;Richardson, Des R;Kovacevic, Zaklina
Affiliation: School of Medical Sciences, University of Sydney, NSW 2006, Australia; Department of Medical Laboratory Sciences, Faculty of Allied Health Sciences, The Hashemite University, Zarqa 13133, Jordan.
Connie Johnson Breast Cancer Research Laboratory, Garvan Institute of Medical Research, NSW 2010 Australia.
Olivia Newton-John Cancer Research Institute
Cancer Drug Resistance and Stem Cell Program, School of Medical Sciences, University of Sydney, NSW 2006, Australia.
Centre for Cancer Cell Biology and Drug Discovery, Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane 4111, Queensland, Australia.
Breast Cancer Group, The Westmead Institute for Medical Research and Westmead Clinical School, University of Sydney, NSW 2145 Australia.
School of Cancer Medicine, La Trobe University, Bundoora, 3086 VIC, Australia.
Centre for Cancer Cell Biology and Drug Discovery, Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane 4111, Queensland, Australia.
Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
School of Medical Sciences, University of Sydney, NSW 2006, Australia
Department of Physiology, School of Biomedical Sciences, University of NSW, NSW 2052 Australia.
Issue Date: Jul-2023
Date: 2023
Publication information: Pharmacological Research 2023-07; 193
Abstract: 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.
DOI: 10.1016/j.phrs.2023.106806
Journal: Pharmacological Research
Start page: 106806
PubMed URL: 37244387
ISSN: 1096-1186
Type: Journal Article
Subjects: Estrogen receptor
Molecular pharmacology
Breast Neoplasms/drug therapy
Breast Neoplasms/metabolism
Progesterone/therapeutic use
Androgens/therapeutic use
Prolactin/therapeutic use
Thiosemicarbazones/therapeutic use
Estrogens/therapeutic use
Appears in Collections:Journal articles

Show full item record

Page view(s)

checked on Dec 10, 2023

Google ScholarTM


Items in AHRO are protected by copyright, with all rights reserved, unless otherwise indicated.