Cytotoxic and radiosensitising effects of a novel thioredoxin reductase inhibitor in breast cancer.

Publisher: Springer Country of Publication: United States NLM ID: 8309330 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1573-0646 (Electronic) Linking ISSN: 01676997 NLM ISO Abbreviation: Invest New Drugs Subsets: MEDLINE

Publication: New York : Springer
Original Publication: Boston : M. Nijhoff, 1983-

Antineoplastic Agents/*pharmacology ; Breast Neoplasms/*pathology ; Drug Resistance, Neoplasm/*drug effects ; Indolequinones/*pharmacology ; Radiation-Sensitizing Agents/*pharmacology ; Thioredoxin-Disulfide Reductase/*antagonists & inhibitors; Cell Line, Tumor ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; Humans ; Inhibitory Concentration 50 ; Thioredoxins/drug effects ; Triple Negative Breast Neoplasms/pathology

Radiotherapy is an effective treatment modality for breast cancer but, unfortunately, not all patients respond fully with a significant number experiencing local recurrences. Overexpression of thioredoxin and thioredoxin reductase has been reported to cause multidrug and radiation resistance - their inhibition may therefore improve therapeutic efficacy. Novel indolequinone compounds have been shown, in pancreatic cancer models, to inhibit thioredoxin reductase activity and exhibit potent anticancer activity. The present study evaluates, using in vitro breast cancer models, the efficacy of a novel indolequinone compound (IQ9) as a single agent and in combination with ionising radiation using a variety of endpoint assays including cell proliferation, clonogenic survival, enzyme activity, and western blotting. Three triple-negative breast cancer (MDA-MB-231, MDA-MB-468, and MDA-MB-436) and two luminal (MCF-7 and T47D) breast cancer cell lines were used. Results show that treatment with IQ9 significantly inhibited thioredoxin reductase activity, and inhibited cell growth and colony formation of breast cancer cells with IC 50 values in the low micromolar ranges. Enhanced radiosensitivity of triple-negative breast cancer cells was observed, with sensitiser enhancement ratios of 1.20-1.43, but with no evident radiosensitisation of luminal breast cancer cell lines. IQ9 upregulated protein expression of thioredoxin reductase in luminal but not in triple-negative breast cancer cells which may explain the observed differential radiosensitisation. This study provides important evidence of the roles of the thioredoxin system as an exploitable radiobiological target in breast cancer cells and highlights the potential therapeutic value of indolequinones as radiosensitisers.***This study was not part of a clinical trial. Clinical trial registration number: N/A.
(© 2021. The Author(s).)

Br J Cancer. 2009 Jul 7;101(1):38-47. (PMID: 19513066)
Trends Pharmacol Sci. 2017 Sep;38(9):794-808. (PMID: 28648527)
Cancers (Basel). 2019 Jul 08;11(7):. (PMID: 31288436)
Methods Enzymol. 1995;252:199-208. (PMID: 7476354)
BMC Cancer. 2019 Aug 30;19(1):865. (PMID: 31470801)
Food Chem Toxicol. 2019 Dec;134:110834. (PMID: 31577924)
Sci Rep. 2019 Jul 31;9(1):11134. (PMID: 31366901)
Mol Pharmacol. 2012 Mar;81(3):401-10. (PMID: 22147753)
Oncotarget. 2014 Dec 30;5(24):12936-49. (PMID: 25427448)
J Exp Clin Cancer Res. 2018 Apr 23;37(1):87. (PMID: 29688867)
Cell Death Dis. 2016 Jun 09;7(6):e2253. (PMID: 27277675)
Mol Cancer Ther. 2016 Oct;15(10):2302-2313. (PMID: 27474148)
Mol Pharmacol. 2003 Sep;64(3):714-20. (PMID: 12920209)
Mol Cell Biol. 2005 Mar;25(5):1980-8. (PMID: 15713651)
PLoS One. 2013;8(1):e53945. (PMID: 23342042)
Mol Cancer Ther. 2006 Jul;5(7):1702-9. (PMID: 16891456)
EMBO J. 1998 May 1;17(9):2596-606. (PMID: 9564042)
J Cell Mol Med. 2012 Jul;16(7):1593-605. (PMID: 22003958)
Biomed Pharmacother. 2017 Oct;94:974-981. (PMID: 28810535)
Radiat Res. 2016 Oct;186(4):385-395. (PMID: 27643875)
Nature. 1997 Apr 24;386(6627):804-10. (PMID: 9126738)
Antioxid Redox Signal. 2013 Oct 10;19(11):1266-303. (PMID: 23244617)
Med Res Rev. 2021 Jan;41(1):342-394. (PMID: 32981100)
Lancet Oncol. 2018 Jan;19(1):27-39. (PMID: 29242041)
Expert Opin Drug Discov. 2011 Feb;6(2):195-203. (PMID: 22647136)
Eur J Med Chem. 2014 Sep 12;84:335-42. (PMID: 25036792)
Clin Oncol (R Coll Radiol). 2014 May;26(5):289-300. (PMID: 24581945)
Arterioscler Thromb Vasc Biol. 2010 Nov;30(11):2089-98. (PMID: 20798378)
Semin Cancer Biol. 2006 Dec;16(6):420-6. (PMID: 17092741)
Front Mol Biosci. 2020 Oct 06;7:586146. (PMID: 33134322)
Clin Biochem. 2010 Nov;43(16-17):1287-93. (PMID: 20713039)
Oncotarget. 2015 Jun 20;6(17):15410-24. (PMID: 25945832)
Radiother Oncol. 2014 Jul;112(1):140-4. (PMID: 24833561)
Cancer Chemother Pharmacol. 2016 Sep;78(3):447-64. (PMID: 27217046)
Sci Rep. 2017 Mar 24;7:42928. (PMID: 28338004)
Biochim Biophys Acta. 2009 Jun;1790(6):495-526. (PMID: 19364476)
Oncogene. 2004 Feb 26;23(8):1599-607. (PMID: 14985701)
Biochem Pharmacol. 2020 May;175:113873. (PMID: 32092292)
Clin Cancer Res. 2005 Dec 1;11(23):8425-30. (PMID: 16322305)
J Med Chem. 2018 May 24;61(10):4273-4282. (PMID: 29112446)
Chemistry. 2020 Aug 12;26(45):10175-10184. (PMID: 32097513)
CA Cancer J Clin. 2018 Nov;68(6):394-424. (PMID: 30207593)
PLoS One. 2014 Jan 22;9(1):e84991. (PMID: 24465461)
Elife. 2017 Apr 11;6:. (PMID: 28398198)
Mol Pharmacol. 2009 Jul;76(1):163-72. (PMID: 19364812)
Med Res Rev. 2019 Jan;39(1):5-39. (PMID: 29727025)
Int J Oncol. 2016 Aug;49(2):753-62. (PMID: 27278553)
Mol Cell. 1999 Dec;4(6):1093-9. (PMID: 10635334)
Br J Pharmacol. 2013 Jan;168(1):11-8. (PMID: 22509926)
FEBS Lett. 2011 Oct 20;585(20):3328-36. (PMID: 21963718)

Keywords: Breast cancer; Indolequinone; Radiosensitivity; Thioredoxin reductase

0 (Antineoplastic Agents)
0 (IQ9 indolequinone)
0 (Indolequinones)
0 (Radiation-Sensitizing Agents)
52500-60-4 (Thioredoxins)
EC 1.8.1.9 (Thioredoxin-Disulfide Reductase)

Date Created: 20210326 Date Completed: 20220202 Latest Revision: 20220907

20221213

PMC8426295

10.1007/s10637-021-01106-5

33768386