2. Academic Validation
  3. Induction of mitochondrial dysfunction as a strategy for targeting tumour cells in metabolically compromised microenvironments

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

  • Nat Commun. 2014;5:3295. doi: 10.1038/ncomms4295.
Xiaonan Zhang 1,  Mårten Fryknäs 2,  Emma Hernlund 3,  Walid Fayad 1,  Angelo De Milito 3,  Maria Hägg Olofsson 3,  Vladimir Gogvadze 4,  Long Dang 5,  Sven Påhlman 6,  Leoni A Kunz Schughart 7,  Linda Rickardson 8,  Padraig D'Arcy 3,  Joachim Gullbo 9,  Peter Nygren 10,  Rolf Larsson 8,  Stig Linder 11
Affiliations

Affiliations

  • 1 1] Department of Oncology-Pathology, Karolinska Institute, Stockholm S-171 76, Sweden [2].
  • 2 1] Division of Clinical Pharmacology, Department of Medical Sciences, Uppsala University, Uppsala S-751 85, Sweden [2].
  • 3 Department of Oncology-Pathology, Karolinska Institute, Stockholm S-171 76, Sweden.
  • 4 Division of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm 171 77, Sweden.
  • 5 Division of Hematology/Oncology, Department of Internal Medicine, University of Florida Shands Cancer Center, University of Florida, Gainesville, Florida 32601, USA.
  • 6 Department of Laboratory Medicine, Center for Molecular Pathology, CREATE Health, Skåne University Hospital, Lund University, S-20502, Malmö, Sweden.
  • 7 OncoRay-National Center for Radiation Research in Oncology, TU Dresden, Dresden 01307, Germany.
  • 8 Division of Clinical Pharmacology, Department of Medical Sciences, Uppsala University, Uppsala S-751 85, Sweden.
  • 9 1] Division of Clinical Pharmacology, Department of Medical Sciences, Uppsala University, Uppsala S-751 85, Sweden [2] Division of Oncology, Department of Radiology, Oncology and Radiation Science, Uppsala University, Uppsala S-751 85, Sweden.
  • 10 Division of Oncology, Department of Radiology, Oncology and Radiation Science, Uppsala University, Uppsala S-751 85, Sweden.
  • 11 1] Department of Oncology-Pathology, Karolinska Institute, Stockholm S-171 76, Sweden [2] Division of Clinical Pharmacology, Department of Medical Sciences, Uppsala University, Uppsala S-751 85, Sweden.
PMID: 24548894 DOI: 10.1038/ncomms4295
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.

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