Journal
CELL CHEMICAL BIOLOGY
Volume 25, Issue 11, Pages 1337-+Publisher
CELL PRESS
DOI: 10.1016/j.chembiol.2018.07.010
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Funding
- Independent Research Fund Denmark (Sapere Aude 2 grant) [6110-00600A]
- Lundbeck Foundation [R105-9308]
- Novo Nordisk Foundation [NNF16OC0020164]
- Danish Cancer Society [R124-A7832-B1086, R90-A6196]
- Carlsberg Foundation [CF15-0431]
- Lundbeck Foundation [R105-2011-9308] Funding Source: researchfish
- Novo Nordisk Fonden [NNF16OC0020164] Funding Source: researchfish
- The Danish Cancer Society [R124-A7832] Funding Source: researchfish
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The natural product family of macrocyclic lipodepsipeptides containing the 4-amido-2,4-pentadienoate functionality possesses intriguing cytotoxic selectivity toward hypoxic cancer cells. These subpopulations of cancer cells display increased metastatic potential and resistance to chemo- and radiotherapy. In this paper, we present studies on the mechanism of action of these natural products in hypoxic cancer cells and show that this involves rapid and hypoxia-selective collapse of mitochondria! integrity and function. These events drive a regulated cell death process that potentially could function as a powerful tool in the fight against chemo- and radiotherapy-resistant cancer cells. Toward that end, we demonstrate activity in two different mouse tumor models.
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