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Cell Chem Biol. 2018 Nov 15;25(11):1337-1349.e12. doi: 10.1016/j.chembiol.2018.07.010. Epub 2018 Aug 16.

APD-Containing Cyclolipodepsipeptides Target Mitochondrial Function in Hypoxic Cancer Cells.

Author information

1
Department of Chemistry, Aarhus University, 8000 Aarhus C, Denmark.
2
Department of Engineering, Aarhus University, 8000 Aarhus C, Denmark.
3
Department of Forensic Medicine, Aarhus University, 8200 Aarhus N, Denmark.
4
Department of Molecular Medicine (MOMA), Aarhus University Hospital, 8200 Aarhus N, Denmark.
5
Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, Denmark.
6
Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark.
7
Research Unit for Molecular Medicine, Department of Clinical Medicine, Aarhus University and University Hospital, 8200 Aarhus N, Denmark.
8
Department of Molecular Medicine (MOMA), Aarhus University Hospital, 8200 Aarhus N, Denmark; Bioinformatics Research Center, BiRC, Aarhus University, 8000 Aarhus C, Denmark.
9
Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, Denmark; Interdisciplinary Nanoscience Center, iNANO, Aarhus University, 8000 Aarhus C, Denmark.
10
Department of Nuclear Medicine and PET Center, Aarhus University Hospital, 8200 Aarhus N, Denmark.
11
Department of Experimental Clinical Oncology, Aarhus University Hospital, 8000 Aarhus C, Denmark.
12
Department of Chemistry, Aarhus University, 8000 Aarhus C, Denmark. Electronic address: thpou@chem.au.dk.

Abstract

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 mitochondrial 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.

KEYWORDS:

ROS; cell death; mitochondria; mode of action; natural products; tumor hypoxia

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