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Iron chelators target both proliferating and quiescent cancer cells
Uppsala University, Sweden.
Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden.
Beactica, Sweden.
Uppsala University, Sweden.
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2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 38343Article in journal (Refereed) Published
Abstract [en]

Poorly vascularized areas of solid tumors contain quiescent cell populations that are resistant to cell cycle-active cancer drugs. The compound VLX600 was recently identified to target quiescent tumor cells and to inhibit mitochondrial respiration. We here performed gene expression analysis in order to characterize the cellular response to VLX600. The compound-specific signature of VLX600 revealed a striking similarity to signatures generated by compounds known to chelate iron. Validation experiments including addition of ferrous and ferric iron in excess, EXAFS measurements, and structure activity relationship analyses showed that VLX600 chelates iron and supported the hypothesis that the biological effects of this compound is due to iron chelation. Compounds that chelate iron possess anti-cancer activity, an effect largely attributed to inhibition of ribonucleotide reductase in proliferating cells. Here we show that iron chelators decrease mitochondrial energy production, an effect poorly tolerated by metabolically stressed tumor cells. These pleiotropic features make iron chelators an attractive option for the treatment of solid tumors containing heterogeneous populations of proliferating and quiescent cells.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2016. Vol. 6, article id 38343
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:liu:diva-133733DOI: 10.1038/srep38343ISI: 000389738800001PubMedID: 27924826OAI: oai:DiVA.org:liu-133733DiVA, id: diva2:1063842
Note

Funding Agencies|Swedish Research Council; Knut och Alice Wallenbergs Stiftelse; Cancerforeningen in Stockholm; Cancerfonden; Vetenskapsradet; Barncancerfonden

Available from: 2017-01-11 Created: 2017-01-09 Last updated: 2018-01-13

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