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

Faten Shehadeh-Tout; Heloisa H Milioli; Suraya Roslan; Patric J Jansson; Mahendiran Dharmasivam; Dinny Graham; Robin Anderson; Tharushi Wijesinghe; Mahan Gholam Azad; Des R Richardson; Zaklina Kovacevic

doi:10.1016/j.phrs.2023.106806

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

Pharmacol Res. 2023 Jul:193:106806. doi: 10.1016/j.phrs.2023.106806. Epub 2023 May 25.

Affiliations

¹ 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.
² Connie Johnson Breast Cancer Research Laboratory, Garvan Institute of Medical Research, NSW 2010 Australia.
³ Metastasis Research Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia.
⁴ Cancer Drug Resistance and Stem Cell Program, School of Medical Sciences, University of Sydney, NSW 2006, Australia.
⁵ Centre for Cancer Cell Biology and Drug Discovery, Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane 4111, Queensland, Australia.
⁶ Breast Cancer Group, The Westmead Institute for Medical Research and Westmead Clinical School, University of Sydney, NSW 2145 Australia.
⁷ Metastasis Research Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia; School of Cancer Medicine, La Trobe University, Bundoora, 3086 VIC, Australia.
⁸ 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. Electronic address: d.richardson@griffith.edu.au.
⁹ School of Medical Sciences, University of Sydney, NSW 2006, Australia; Department of Physiology, School of Biomedical Sciences, University of NSW, NSW 2052 Australia. Electronic address: z.kovacevic@unsw.edu.au.

PMID: 37244387
DOI: 10.1016/j.phrs.2023.106806

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.

Keywords: Estrogen receptor; Molecular pharmacology; Tamoxifen; Thiosemicarbazones.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Androgens / therapeutic use
Breast Neoplasms* / drug therapy
Breast Neoplasms* / metabolism
ErbB Receptors
Estrogens / therapeutic use
Female
Humans
Progesterone / therapeutic use
Prolactin / therapeutic use
Receptors, Prolactin
Tamoxifen / pharmacology
Thiosemicarbazones* / pharmacology
Thiosemicarbazones* / therapeutic use

Substances

Progesterone
Androgens
di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone
Receptors, Prolactin
Prolactin
Tamoxifen
Thiosemicarbazones
ErbB Receptors
Estrogens