title: Induction of mitochondrial dysfunction as a strategy for targeting tumour cells in metabolically compromised microenvironments.
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.
authors.affiliation: 1] Department of Oncology-Pathology, Karolinska Institute, Stockholm S-171 76, Sweden [2].
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: 1] Division of Clinical Pharmacology, Department of Medical Sciences, Uppsala University, Uppsala S-751 85, Sweden [2].
authors.forename: Mårten
authors.initials: M
authors.lastname: Fryknäs
authors.affiliation: Department of Oncology-Pathology, Karolinska Institute, Stockholm S-171 76, Sweden.
authors.forename: Emma
authors.initials: E
authors.lastname: Hernlund
authors.affiliation: 1] Department of Oncology-Pathology, Karolinska Institute, Stockholm S-171 76, Sweden [2].
authors.forename: Walid
authors.initials: W
authors.lastname: Fayad
authors.affiliation: Department of Oncology-Pathology, Karolinska Institute, Stockholm S-171 76, Sweden.
authors.forename: Angelo
authors.initials: A
authors.lastname: De Milito
authors.affiliation: Department of Oncology-Pathology, Karolinska Institute, Stockholm S-171 76, Sweden.
authors.forename: Maria Hägg
authors.initials: MH
authors.lastname: Olofsson
authors.affiliation: Division of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm 171 77, Sweden.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Gogvadze
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, University of Florida Shands Cancer Center, University of Florida, Gainesville, Florida 32601, USA.
authors.forename: Long
authors.initials: L
authors.lastname: Dang
authors.affiliation: Department of Laboratory Medicine, Center for Molecular Pathology, CREATE Health, Skåne University Hospital, Lund University, S-20502, Malmö, Sweden.
authors.forename: Sven
authors.initials: S
authors.lastname: Påhlman
authors.affiliation: OncoRay-National Center for Radiation Research in Oncology, TU Dresden, Dresden 01307, Germany.
authors.forename: Leoni A Kunz
authors.initials: LA
authors.lastname: Schughart
authors.affiliation: Division of Clinical Pharmacology, Department of Medical Sciences, Uppsala University, Uppsala S-751 85, Sweden.
authors.forename: Linda
authors.initials: L
authors.lastname: Rickardson
authors.affiliation: Department of Oncology-Pathology, Karolinska Institute, Stockholm S-171 76, Sweden.
authors.forename: Padraig
authors.initials: P
authors.lastname: D'Arcy
authors.affiliation: 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.
authors.forename: Joachim
authors.initials: J
authors.lastname: Gullbo
authors.affiliation: Division of Oncology, Department of Radiology, Oncology and Radiation Science, Uppsala University, Uppsala S-751 85, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Nygren
authors.affiliation: Division of Clinical Pharmacology, Department of Medical Sciences, Uppsala University, Uppsala S-751 85, Sweden.
authors.forename: Rolf
authors.initials: R
authors.lastname: Larsson
authors.affiliation: 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.
authors.forename: Stig
authors.initials: S
authors.lastname: Linder
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology*; D000860:Hypoxia / Q000139:chemically induced; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects; D018874:Spheroids, Cellular; D014230:Triazoles / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D006835:Hydrazones; D014230:Triazoles; C000602558:VLX600; D005947:Glucose