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Sulfamoylated Estradiol Analogs Targeting the Actin and Microtubule Cytoskeletons Demonstrate Anti-Cancer Properties In Vitro and In Ovo
by
, , , , and
Anne Elisabeth Mercier
1,*,
Anna Margaretha Joubert
1,
Renaud Prudent
2,
Jean Viallet
3,
Agnes Desroches-Castan
4,
Leanne De Koning
5,
Peace Mabeta
1,
Jolene Helena
1,
Michael Sean Pepper
6 and
Laurence Lafanechère
1,7 1
Department of Physiology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria 0028, South Africa
2
Institute for Advanced Biosciences, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, 38000 Grenoble, France
3
Inovotion SAS France, Biopolis, 38700 La Tronche, France
4
Laboratoire Biosanté U1292, Université Grenoble Alpes, Inserm, CEA, 38000 Grenoble, France
5
Institut Curie Centre de Recherche, PSL Research University, 75248 Paris Cedex 05, France
6
Institute for Cellular and Molecular Medicine, Department of Immunology, and South African Medical Research Council Extramural Unit for Stem Cell Research and Therapy, School of Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria 0028, South Africa
7
Team Cytoskeleton Dynamics and Nuclear Functions, Institute for Advanced Biosciences, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, 38000 Grenoble, France
*
Author to whom correspondence should be addressed.
Cancers 2024, 16(17), 2941; https://doi.org/10.3390/cancers16172941
Submission received: 25 June 2024
/
Revised: 30 July 2024
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Accepted: 14 August 2024
/
Published: 23 August 2024
(This article belongs to the Special Issue Cell Signaling in Cancer and Cancer Therapy)
Simple Summary
The naturally occurring derivative of estrogen, 2-methoxyestradiol (2-ME), has been shown to have good anti-cancer properties. However, it is broken down too quickly within the blood to be clinically useful. We designed 2-ME analogs with modifications which could avoid rapid metabolism, would preferably stay in the tumor, and were more toxic to cancer cells. Here, we looked more closely at how these compounds work within cancer cells, and how they communicate within themselves and with their environment. ESE-15-one and ESE-16 interfere with the functioning of the intracellular cytoskeleton (actin and microtubules), sending messages that stop cell division, intracellular transport of proteins, and cell migration and invasion, eventually inducing cell suicide. They also inhibited the movement of cells that make blood vessels that would support tumor growth. Using eggs with chicken embryos, we could show that the compounds reduced the tumor size and diminished the spread of cancer cells in a living system.
Abstract
The microtubule-disrupting agent 2-methoxyestradiol (2-ME) displays anti-tumor and anti-angiogenic properties, but its clinical development is halted due to poor pharmacokinetics. We therefore designed two 2-ME analogs in silico—an ESE-15-one and an ESE-16 one—with improved pharmacological properties. We investigated the effects of these compounds on the cytoskeleton in vitro, and their anti-angiogenic and anti-metastatic properties in ovo. Time-lapse fluorescent microscopy revealed that sub-lethal doses of the compounds disrupted microtubule dynamics. Phalloidin fluorescent staining of treated cervical (HeLa), metastatic breast (MDA-MB-231) cancer, and human umbilical vein endothelial cells (HUVECs) displayed thickened, stabilized actin stress fibers after 2 h, which rearranged into a peripheral radial pattern by 24 h. Cofilin phosphorylation and phosphorylated ezrin/radixin/moesin complexes appeared to regulate this actin response. These signaling pathways overlap with anti-angiogenic, extra-cellular communication and adhesion pathways. Sub-lethal concentrations of the compounds retarded both cellular migration and invasion. Anti-angiogenic and extra-cellular matrix signaling was evident with TIMP2 and P-VEGF receptor-2 upregulation. ESE-15-one and ESE-16 exhibited anti-tumor and anti-metastatic properties in vivo, using the chick chorioallantoic membrane assay. In conclusion, the sulfamoylated 2-ME analogs displayed promising anti-tumor, anti-metastatic, and anti-angiogenic properties. Future studies will assess the compounds for myeloproliferative effects, as seen in clinical applications of other drugs in this class.
