2. Academic Validation
  3. Effects of tyrosine kinase inhibitors on androgen, estrogen α, glucocorticoid and thyroid receptors

Effects of tyrosine kinase inhibitors on androgen, estrogen α, glucocorticoid and thyroid receptors

  • Toxicol Appl Pharmacol. 2022 Jan 1;434:115818. doi: 10.1016/j.taap.2021.115818.
Maša Kenda 1,  Damjan Avsec 2,  Taja Zore 3,  Eva Kogovšek 4,  Urša Pečar Fonović 5,  Janko Kos 6,  Krištof Bozovičar 7,  Tomaž Bratkovič 8,  Nataša Karas Kuželički 9,  Bojana Žegura 10,  Metka Filipič 11,  Marija Sollner Dolenc 12
Affiliations

Affiliations

  • 1 University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI-1000 Ljubljana, Slovenia. Electronic address: masa.kenda@ffa.uni-lj.si.
  • 2 University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI-1000 Ljubljana, Slovenia. Electronic address: damjan.avsec@ffa.uni-lj.si.
  • 3 University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI-1000 Ljubljana, Slovenia. Electronic address: taja.zore@ffa.uni-lj.si.
  • 4 University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI-1000 Ljubljana, Slovenia.
  • 5 University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI-1000 Ljubljana, Slovenia. Electronic address: ursa.pecarfonovic@ffa.uni-lj.si.
  • 6 University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI-1000 Ljubljana, Slovenia. Electronic address: janko.kos@ffa.uni-lj.si.
  • 7 University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI-1000 Ljubljana, Slovenia. Electronic address: kristof.bozovicar@ffa.uni-lj.si.
  • 8 University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI-1000 Ljubljana, Slovenia. Electronic address: tomaz.bratkovic@ffa.uni-lj.si.
  • 9 University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI-1000 Ljubljana, Slovenia. Electronic address: natasa.karaskuzelicki@ffa.uni-lj.si.
  • 10 National Institute of Biology, Department of Genetic Toxicology and Cancer Biology, Večna pot 111, SI-1000 Ljubljana, Slovenia. Electronic address: bojana.zegura@nib.si.
  • 11 National Institute of Biology, Department of Genetic Toxicology and Cancer Biology, Večna pot 111, SI-1000 Ljubljana, Slovenia. Electronic address: metka.filipic@nib.si.
  • 12 University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI-1000 Ljubljana, Slovenia. Electronic address: marija.sollner@ffa.uni-lj.si.
PMID: 34890638 DOI: 10.1016/j.taap.2021.115818
Abstract

Modern Anticancer therapies favor a targeted approach. Tyrosine kinase inhibitors (TKIs) are drugs that target molecular pathways involved in various types of malignancies. Although TKIs are safe and well tolerated, they remain not completely selective; e.g., endocrine-mediated adverse events have been observed with their use. In the present study, the effects of seven TKIs were determined on the activities of Androgen Receptor, Estrogen Receptor α (ERα), Glucocorticoid Receptor and thyroid receptor in vitro using stably transfected cell lines expressing firefly luciferase reporter gene: AR-EcoScreen, hERα-HeLa9903, MDA-kb2, and GH3.TRE-Luc cells, respectively. Antiandrogenic activity was seen for erlotinib, estrogenic activity for imatinib, antiestrogenic activity for dasatinib, erlotinib, nilotinib, regorafenib and sorafenib, glucocorticoid activity for erlotinib and ibrutinib, antiglucocorticoid activity for regorafenib and sorafenib, and antithyroid activity for ibrutinib. Additionally, synergism was seen for 1-5 μM dasatinib and 500 nM hydrocortisone combination for glucocorticoid activity in MDA-kb2 cells. The estrogenic activity of imatinib was confirmed as mediated through ERα, and interference of the TKIs with the reporter gene assays was ruled out in a cell-lysate-based firefly luciferase Enzyme inhibition assay. Imatinib in combination with 4-hydroxytamoxifen showed concentration-dependent effects on the metabolic activity of ERα-expressing AN3CA, MCF-7, and SKOV3 cells, and on cell proliferation and adhesion of MCF-7 cells. These findings contribute to the understanding of the endocrine effects of TKIs, in terms of toxicity and effectiveness, and define the need to further evaluate the endocrine disrupting activities of TKIs to safeguard human and environmental health.

Keywords

Cell adhesion; Cell proliferation; Endocrine disruption; Hormonal effects; Nuclear receptors; Tyrosine kinase inhibitors.

Figures
Products