APD-Containing Cyclolipodepsipeptides Target Mitochondrial Function in Hypoxic Cancer Cells. Issue 11 (15th November 2018)

• Record Type: Journal Article
• Authors: Jacobsen, Kristian Mark; Villadsen, Nikolaj Lilholm; Tørring, Thomas; Nielsen, Camilla Bak; Salomón, Trine; Nielsen, Morten Muhlig; Tsakos, Michail; Sibbersen, Christian; Scavenius, Carsten; Nielsen, Rikke; Christensen, Erik Ilsø; Guerra, Paula Fernandez; Bross, Peter; Pedersen, Jakob Skou; Enghild, Jan Johannes; Johannsen, Mogens; Frøkiær, Jørgen; Overgaard, Jens; Horsman, Michael R.; Busk, Morten; Poulsen, Thomas B.
• Is Part Of: Cell chemical biology. Volume 25:Issue 11(2018)
• Page Start: 1337
• Page End: 1349.e12
• Publication Date: 2018-11-15
• Subjects: cell death -- tumor hypoxia -- mode of action -- ROS -- natural products -- mitochondria; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2018.07.010
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: 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. Graphical Abstract: Highlights: APD-CLDs induce a rapid loss of mitochondrial ultrastructure and function Toxicity is mechanistically distinct from other hypoxia-activated compounds APD-CLD-induced cell death is dependent on oxygen concentration The APD-CLDs are potently active in vivo Abstract : Hypoxic cancer cells constitute a major challenge in chemo- and radiotherapy and demand the development of hypoxia-selective drugs. Here, Jacobsen et al. present comprehensive biological evaluation of a natural product family that induces selective cell death in hypoxic cancer cells by rapidly impeding mitochondrial function.