Induction of mitochondrial dysfunction as a strategy for targeting tumour cells in metabolically compromised microenvironments

Xiaonan Zhang, Mårten Fryknäs, Emma Hernlund, Walid Fayad, Angelo De Milito, Maria Hägg Olofsson, Vladimir Gogvadze, Long Dang, Sven Påhlman, Leoni A. Kunz Schughart, Linda Rickardson, Padraig D′Arcy, Joachim Gullbo, Peter Nygren, Rolf Larsson and Stig Linder ()
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Xiaonan Zhang: Karolinska Institute
Mårten Fryknäs: Uppsala University
Emma Hernlund: Karolinska Institute
Walid Fayad: Karolinska Institute
Angelo De Milito: Karolinska Institute
Maria Hägg Olofsson: Karolinska Institute
Vladimir Gogvadze: Institute of Environmental Medicine, Karolinska Institutet
Long Dang: University of Florida Shands Cancer Center, University of Florida
Sven Påhlman: Center for Molecular Pathology, CREATE Health, Skåne University Hospital, Lund University
Leoni A. Kunz Schughart: OncoRay—National Center for Radiation Research in Oncology, TU Dresden
Linda Rickardson: Uppsala University
Padraig D′Arcy: Karolinska Institute
Joachim Gullbo: Uppsala University
Peter Nygren: Oncology and Radiation Science, Uppsala University
Rolf Larsson: Uppsala University
Stig Linder: Karolinska Institute

Nature Communications, 2014, vol. 5, issue 1, 1-14

Abstract: Abstract 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.

Date: 2014
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DOI: 10.1038/ncomms4295

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