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

Zhang, Xiaonan; Fryknäs, Mårten; Hernlund, Emma; Fayad, Walid; De Milito, Angelo; Olofsson, Maria Hägg; Gogvadze, Vladimir; Dang, Long; Påhlman, Sven LU and Schughart, Leoni A Kunz, et al. (2014) In Nature Communications 5(Feb 18).
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... (More)
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. (Less)
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Nature Communications
volume
5
issue
Feb 18
publisher
Nature Publishing Group
external identifiers
  • pmid:24548894
  • wos:000332667600042
  • scopus:84894542141
ISSN
2041-1723
DOI
10.1038/ncomms4295
language
English
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yes
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e48e8c48-53bc-4543-a474-bd0e5084d4a0 (old id 4334498)
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http://www.ncbi.nlm.nih.gov/pubmed/24548894?dopt=Abstract
date added to LUP
2014-03-05 22:07:06
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2017-11-05 03:50:42
@article{e48e8c48-53bc-4543-a474-bd0e5084d4a0,
  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.},
  articleno    = {3295},
  author       = {Zhang, Xiaonan and Fryknäs, Mårten and Hernlund, Emma and Fayad, Walid and De Milito, Angelo and Olofsson, Maria Hägg and Gogvadze, Vladimir and Dang, Long and Påhlman, Sven and Schughart, Leoni A Kunz and Rickardson, Linda and D Arcy, Padraig and Gullbo, Joachim and Nygren, Peter and Larsson, Rolf and Linder, Stig},
  issn         = {2041-1723},
  language     = {eng},
  number       = {Feb 18},
  publisher    = {Nature Publishing Group},
  series       = {Nature Communications},
  title        = {Induction of mitochondrial dysfunction as a strategy for targeting tumour cells in metabolically compromised microenvironments.},
  url          = {http://dx.doi.org/10.1038/ncomms4295},
  volume       = {5},
  year         = {2014},
}