Several commercially available triorganotin compounds were previously found to function as agonist ligands for nuclear retinoid X receptor (RXR) molecules. Triphenyltin isoselenocyanate (TPT-NCSe), a novel selenium atom containing a derivative of triorganotin origin, was found to represent a new cognate bioactive ligand for RXRs. TPT-NCSe displayed a concentration- and time-dependent decrease in the cell viability in both human breast carcinoma MCF-7 (estrogen receptor positive) and MDA‑MB‑231 (triple negative) cell lines. Reactive oxygen species levels generated in response to TPT-NCSe were significantly higher in both carcinoma cell lines treated with TPT-NCSe when compared to mock-treated samples. Treatment with 500 nM TPT-NCSe caused a decrease in SOD1 and increased SOD2 mRNA in MCF-7 cells. The levels of SOD2 mRNA were more increased following the treatment with TPT-NCSe along with 1 μM all-trans retinoic acid (AtRA) in MCF-7 cells. An increased superoxide dismutase SOD1 and SOD2 mRNA levels were also detected in combination treatment of 500 nM TPT-NCSe and 1 μM AtRA in TPT-NCSe-treated MDA-MB-231 cells. The data have also shown that TPT-NCSe induces apoptosis via a caspase cascade triggered by the mitochondrial apoptotic pathway. TPT-NCSe modulates the expression levels of apoptosis‑related proteins, Annexin A5, Bcl‑2 and BAX family proteins, and finally, it enhances the expression levels of its cognate nuclear receptor subtypes RXRalpha and RXRbeta.

Department of Chemical Drugs Faculty of Pharmacy Masaryk University Palackého třída 1946 1 612 00 Brno Czech Republic

Department of Pharmaceutical and Medicinal Chemistry Institute of Pharmacy Paracelsus Medical University Strubergasse 21 5020 Salzburg Austria

Institute of Experimental Endocrinology Biomedical Research Center Slovak Academy of Sciences Dúbravská cesta 9 845 05 Bratislava Slovak Republic

See more in PubMed

Gielen M, Biesemans M, de Vos D, Willem R (2000) Synthesis, characterization and in vitro antitumor activity of di- and triorganotin derivatives of polyoxa- and biologically relevant carboxylic acids. J Inorg Biochem 79:139–145 PubMed

Tabassum S, Pettinari C (2006) Chemical and biotechnological developments in organotin cancer chemotherapy. J Organomet Chem 691:1761–1766

Barbieri F, Sparatore F, Cagnoli M, Bruzzo C, Novelli F, Alama A (2001) Antiproliferative activity and interactions with cell-cycle related proteins of the organotin compound triethyltin(IV)lupinylsulfide hydrochloride. Chem Biol Interact 134:27–39 PubMed

Barbieri F, Viale M, Sparatore F, Schettini G, Favre A, Bruzzo C, Novelli F, Alama A (2002) Antitumor activity of a new orally active organotin compound: a preliminary study in murine tumour models. Anticancer Drugs 13:599–604 PubMed

Hunakova L, Horvathova E, Majerova K, Bobal P, Otevrel J, Brtko J (2019) Genotoxic effects of tributyltin and triphenyltin isothiocyanates, cognate RXR ligands: comparison in human breast carcinoma MCF 7 and MDA-MB-231 cells. Int J Mol Sci. 10.3390/ijms20051198 PubMed PMC

Alama A, Tasso B, Novelli F, Sparatore F (2009) Organometallic compounds in oncology: implications of novel organotins as antitumor agents. Drug Discov Today 14:500–508 PubMed

Brtko J, Dvorak Z (2015) Triorganotin compounds–ligands for “rexinoid” inducible transcription factors: biological effects. Toxicol Lett 234:50–58 PubMed

Nakanishi T, Nishikawa J, Hiromori Y, Yokoyama H, Koyanagi M, Takasuga S, Ishizaki J, Watanabe M, Isa S, Utoguchi N, Itoh N, Kohno Y, Nishihara T, Tanaka K (2005) Trialkyltin compounds bind retinoid X receptor to alter human placental endocrine functions. Mol Endocrinol 19:2502–2516 PubMed

Toporova L, Macejova D, Brtko J (2016) Radioligand binding assay for accurate determination of nuclear retinoid X receptors: a case of triorganotin endocrine disrupting ligands. Toxicol Lett 254:32–36 PubMed

Brtko J, Dvorak Z (2020) Natural and synthetic retinoid X receptor ligands and their role in selected nuclear receptor action. Biochimie 179:157–168 PubMed

le Maire A, Rey M, Vivat V, Guee L, Blanc P, Malosse C, Chamot-Rooke J, Germain P, Bourguet W (2022) Design and in vitro characterization of RXR variants as tools to investigate the biological role of endogenous rexinoids. J Mol Endocrinol 69:377–390 PubMed

Hunakova L, Horvathova E, Matuskova M, Bobal P, Otevrel J, Brtko J (2022) In vitro antiproliferative and cytotoxic activities of novel triphenyltin isoselenocyanate in human breast carcinoma cell lines MCF 7 and MDA-MB-231. Med Oncol 39:99 PubMed

Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63 PubMed

Macejova D, Podoba J, Toporova L, Grigerova M, Kajo K, Machalekova K, Brtko J (2019) Causal associations of autoimmune thyroiditis and papillary thyroid carcinoma: mRNA expression of selected nuclear receptors and other molecular targets. Oncol Lett 18:4270–4277 PubMed PMC

Schrödinger small-molecule drug discovery suite 20-3. Glide, version 88139 ed. Schrödinger, LLC, 2020

Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE (2000) The protein data bank. Nucleic Acids Res 28:235–242 PubMed PMC

le Maire A, Bourguet W, Balaguer P (2010) A structural view of nuclear hormone receptor: endocrine disruptor interactions. Cell Mol Life Sci 67:1219–1237 PubMed PMC

le Maire A, Grimaldi M, Roecklin D, Dagnino S, Vivat-Hannah V, Balaguer P, Bourguet W (2009) Activation of RXR-PPAR heterodimers by organotin environmental endocrine disruptors. EMBO Rep 10:367–373 PubMed PMC

Schrödinger small-molecule drug discovery suite 20-3. Epik, version 5.3 ed. Schrödinger, LLC, 2020.

Zhao Y, Truhlar DG (2008) The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals. Theor Chem Acc 120:215–241

Gilson MK, Davis ME, Luty BA, Mccammon JA (1993) Computation of electrostatic forces on solvated molecules using the Poisson-Boltzmann equation. J Phys Chem-Us 97:3591–3600 PubMed

Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, Repasky MP, Knoll EH, Shelley M, Perry JK, Shaw DE, Francis P, Shenkin PS (2004) Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem 47:1739–1749 PubMed

Halgren TA, Murphy RB, Friesner RA, Beard HS, Frye LL, Pollard WT, Banks JL (2004) Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J Med Chem 47:1750–1759 PubMed

Kupcho K, Shultz J, Hurst R, Hartnett J, Zhou W, Machleidt T, Grailer J, Worzella T, Riss T, Lazar D, Cali JJ, Niles A (2019) A real-time, bioluminescent annexin V assay for the assessment of apoptosis. Apoptosis 24:184–197 PubMed PMC

Eskandari E, Eaves CJ (2022) Paradoxical roles of caspase-3 in regulating cell survival, proliferation, and tumorigenesis. J Cell Biol. 10.1083/jcb.202201159 PubMed PMC

Anson F, Thayumanavan S, Hardy JA (2021) Exogenous introduction of initiator and executioner caspases results in different apoptotic outcomes. JACS Au 1:1240–1256 PubMed PMC

Redza-Dutordoir M, Averill-Bates DA (2016) Activation of apoptosis signalling pathways by reactive oxygen species. Biochim Biophys Acta 1863:2977–2992 PubMed

Brand MD, Nicholls DG (2011) Assessing mitochondrial dysfunction in cells. Biochem J 435:297–312 PubMed PMC

Hernansanz-Agustin P, Enriquez JA (2021) Generation of reactive oxygen species by mitochondria. Antioxidants (Basel) 10:415 PubMed PMC

Weitsman GE, Ravid A, Liberman UA, Koren R (2003) Vitamin D enhances caspase-dependent and-independent TNFalpha-induced breast cancer cell death: the role of reactive oxygen species and mitochondria. Int J Cancer 106:178–186 PubMed

Papa L, Hahn M, Marsh EL, Evans BS, Germain D (2014) SOD2 to SOD1 switch in breast cancer. J Biol Chem 289:5412–5416 PubMed PMC

Kim YS, Gupta Vallur P, Phaeton R, Mythreye K, Hempel N (2017) Insights into the dichotomous regulation of SOD2 in cancer. Antioxidants (Basel). 10.3390/antiox6040086 PubMed PMC

Kiningham KK, Cardozo ZA, Cook C, Cole MP, Stewart JC, Tassone M, Coleman MC, Spitz DR (2008) All-trans-retinoic acid induces manganese superoxide dismutase in human neuroblastoma through NF-kappaB. Free Radic Biol Med 44:1610–1616 PubMed PMC

Llopis S, Singleton B, Duplessis T, Carrier L, Rowan B, Williams C (2013) Dichotomous roles for the orphan nuclear receptor NURR1 in breast cancer. BMC Cancer 13:139 PubMed PMC

Illes P, Brtko J, Dvorak Z (2015) Development and characterization of a human reporter cell line for the assessment of thyroid receptor transcriptional activity: a case of organotin endocrine disruptors. J Agric Food Chem 63:7074–7083 PubMed

Grun F, Blumberg B (2006) Environmental obesogens: organotins and endocrine disruption via nuclear receptor signaling. Endocrinology 147:S50-55 PubMed

Grun F (2010) Obesogens. Curr Opin Endocrinol Diabetes Obes 17:453–459 PubMed

Eisenberg-Lerner A, Bialik S, Simon HU, Kimchi A (2009) Life and death partners: apoptosis, autophagy and the cross-talk between them. Cell Death Differ 16:966–975 PubMed

Larsson CA, Moyer SM, Liu B, Michel KA, Pant V, Yang P, Wong J, El-Naggar AK, Krahe R, Lozano G (2018) Synergistic and additive effect of retinoic acid in circumventing resistance to p53 restoration. Proc Natl Acad Sci USA 115:2198–2203 PubMed PMC

Garattini E, Bolis M, Garattini SK, Fratelli M, Centritto F, Paroni G, Gianni M, Zanetti A, Pagani A, Fisher JN, Zambelli A, Terao M (2014) Retinoids and breast cancer: From basic studies to the clinic and back again. Cancer Treat Rev 40:739–749 PubMed