Innovative thiosemicarbazones that induce multi-modal mechanisms to down-regulate estrogen-, progesterone-, androgen- and prolactin-receptors in breast cancer
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 d...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-07-01
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| Series: | Pharmacological Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661823001627 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Faten Shehadeh-Tout |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T14:14:04Z |
| format | Article |
| id | doaj.art-dff342b54e2544c989ec6c075f0d2f3f |
| institution | Directory Open Access Journal |
| issn | 1096-1186 |
| language | English |
| last_indexed | 2024-03-12T14:14:04Z |
| publishDate | 2023-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj.art-dff342b54e2544c989ec6c075f0d2f3f2023-08-21T04:20:03ZengElsevierPharmacological Research1096-11862023-07-01193106806Innovative thiosemicarbazones that induce multi-modal mechanisms to down-regulate estrogen-, progesterone-, androgen- and prolactin-receptors in breast cancerFaten Shehadeh-Tout0Heloisa H. Milioli1Suraya Roslan2Patric J. Jansson3Mahendiran Dharmasivam4Dinny Graham5Robin Anderson6Tharushi Wijesinghe7Mahan Gholam Azad8Des R. Richardson9Zaklina Kovacevic10School of Medical Sciences, University of Sydney, NSW 2006, Australia; Department of Medical Laboratory Sciences, Faculty of Allied Health Sciences, The Hashemite University, Zarqa 13133, JordanConnie Johnson Breast Cancer Research Laboratory, Garvan Institute of Medical Research, NSW 2010 AustraliaMetastasis Research Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, AustraliaCancer Drug Resistance and Stem Cell Program, School of Medical Sciences, University of Sydney, NSW 2006, AustraliaCentre for Cancer Cell Biology and Drug Discovery, Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane 4111, Queensland, AustraliaBreast Cancer Group, The Westmead Institute for Medical Research and Westmead Clinical School, University of Sydney, NSW 2145 AustraliaMetastasis Research Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia; School of Cancer Medicine, La Trobe University, Bundoora, 3086 VIC, AustraliaCentre for Cancer Cell Biology and Drug Discovery, Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane 4111, Queensland, AustraliaCentre for Cancer Cell Biology and Drug Discovery, Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane 4111, Queensland, AustraliaCentre 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; Corresponding author at: Centre for Cancer Cell Biology and Drug Discovery, Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane 4111, Queensland, Australia.School of Medical Sciences, University of Sydney, NSW 2006, Australia; Department of Physiology, School of Biomedical Sciences, University of NSW, NSW 2052 Australia; Corresponding author at: Department of Physiology, School of Biomedical Sciences, University of NSW, NSW 2052 Australia.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.http://www.sciencedirect.com/science/article/pii/S1043661823001627Molecular pharmacologyEstrogen receptorTamoxifenThiosemicarbazones |
| spellingShingle | 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 Innovative thiosemicarbazones that induce multi-modal mechanisms to down-regulate estrogen-, progesterone-, androgen- and prolactin-receptors in breast cancer Pharmacological Research Molecular pharmacology Estrogen receptor Tamoxifen Thiosemicarbazones |
| title | Innovative thiosemicarbazones that induce multi-modal mechanisms to down-regulate estrogen-, progesterone-, androgen- and prolactin-receptors in breast cancer |
| title_full | Innovative thiosemicarbazones that induce multi-modal mechanisms to down-regulate estrogen-, progesterone-, androgen- and prolactin-receptors in breast cancer |
| title_fullStr | Innovative thiosemicarbazones that induce multi-modal mechanisms to down-regulate estrogen-, progesterone-, androgen- and prolactin-receptors in breast cancer |
| title_full_unstemmed | Innovative thiosemicarbazones that induce multi-modal mechanisms to down-regulate estrogen-, progesterone-, androgen- and prolactin-receptors in breast cancer |
| title_short | Innovative thiosemicarbazones that induce multi-modal mechanisms to down-regulate estrogen-, progesterone-, androgen- and prolactin-receptors in breast cancer |
| title_sort | innovative thiosemicarbazones that induce multi modal mechanisms to down regulate estrogen progesterone androgen and prolactin receptors in breast cancer |
| topic | Molecular pharmacology Estrogen receptor Tamoxifen Thiosemicarbazones |
| url | http://www.sciencedirect.com/science/article/pii/S1043661823001627 |
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