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Induction of mitochondrial dysfunction as a strategy for targeting tumour cells in metabolically compromised microenvironments
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
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2014 (English)In: Nature Communications, ISSN 2041-1723, Vol. 5, 3295- p.Article in journal (Refereed) Published
Abstract [en]

Abnormal vascularization of solid tumours results in the development of microenvironments deprived of oxygen and nutrients that harbour slowly growing and metabolically stressed cells. Such cells display enhanced resistance to standard chemotherapeutic agents and repopulate tumours after therapy. Here we identify the small molecule VLX600 as a drug that is preferentially active against quiescent cells in colon cancer 3-D microtissues. The anticancer activity is associated with reduced mitochondrial respiration, leading to bioenergetic catastrophe and tumour cell death. VLX600 shows enhanced cytotoxic activity under conditions of nutrient starvation. Importantly, VLX600 displays tumour growth inhibition in vivo. Our findings suggest that tumour cells in metabolically compromised microenvironments have a limited ability to respond to decreased mitochondrial function, and suggest a strategy for targeting the quiescent populations of tumour cells for improved cancer treatment.

Place, publisher, year, edition, pages
2014. Vol. 5, 3295- p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-223578DOI: 10.1038/ncomms4295ISI: 000332667600042OAI: oai:DiVA.org:uu-223578DiVA: diva2:713972
Available from: 2014-04-24 Created: 2014-04-22 Last updated: 2014-04-24Bibliographically approved

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Fryknäs, MårtenRickardson, LindaGullbo, JoachimNygren, PeterLarsson, Rolf
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