Organoruthenium complexes with benzo-fused pyrithiones overcome platinum resistance in ovarian cancer cells

Research output: Contribution to journalArticlepeer-review

Authors

  • Jerneja Kladnik
  • Jakob Kljun
  • Hilke Burmeister
  • Petra Lippman
  • Francesca G Ellis
  • Ingo Ott
  • Iztok Turel

Colleges, School and Institutes

External organisations

  • University of Ljubljana
  • University of Birmingham
  • Technische Universität Braunschweig

Abstract

Drug resistance to existing anticancer agents is a growing clinical concern, with many first line treatments showing poor efficacy in treatment plans of some cancers. Resistance to platinum agents, such as cisplatin, is particularly prevalent in the treatment of ovarian cancer, one of the most common cancers amongst women in the developing world. Therefore, there is an urgent need to develop next generation of anticancer agents which can overcome resistance to existing therapies. We report a new series of organoruthenium(II) complexes bearing structurally modified pyrithione ligands with extended aromatic scaffold, which overcome platinum and adriamycin resistance in human ovarian cancer cells. The mechanism of action of such complexes appears to be unique from that of cisplatin, involving G1 cell cycle arrest without generation of cellular ROS, as is typically associated with similar ruthenium complexes. The complexes inhibit the enzyme thioredoxin reductase (TrxR) in a model system and reduce cell motility towards wound healing. Importantly, this work highlights further development in our understanding of the multi-targeting mechanism of action exhibited by transition metal complexes.

Bibliographic note

Funding Information: Acknowledgments: The authors thank the EN→FIST Centre of Excellence, Dunajska 156, SI-1000 Ljubljana, Slovenia, for the use of a SuperNova diffractometer. This article is based upon work from COST Action STRATAGEM, CA17104, supported by COST (European Cooperation in Science and Technology), www.cost.eu (accessed on 16 May 2021). Funding Information: Funding: This research was funded by Junior Researcher Grant for J.K. (Jerneja Kladnik), the program Grant P1-0175, and bilateral project grant number I-DE/17-19-3 of the Slovenian Research Agency (ARRS).

Details

Original languageEnglish
Article number2493
Number of pages21
JournalCancers
Volume13
Issue number10
Publication statusPublished - 20 May 2021

Keywords

  • ruthenium, pyrithione, resistance to chemotherapy, cancer, ovarian, thioredoxin, Ruthenium, Resistance to chemotherapy, Ovarian, Pyrithione, Thioredoxin, Cancer

ASJC Scopus subject areas

Sustainable Development Goals