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, Stig Linder

Research output: Contribution to journalArticlepeer-review

153 Citations (SciVal)

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.
Original languageEnglish
Article number3295
JournalNature Communications
Volume5
Issue numberFeb 18
DOIs
Publication statusPublished - 2014

Subject classification (UKÄ)

  • Cancer and Oncology

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