APD-Containing Cyclolipodepsipeptides Target Mitochondrial Function in Hypoxic Cancer Cells

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Cell Line, Tumor
  • Depsipeptides / chemistry*
  • Depsipeptides / pharmacology*
  • Depsipeptides / therapeutic use
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Neoplasms / drug therapy
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Reactive Oxygen Species / metabolism
  • Tumor Hypoxia / drug effects*


  • Antineoplastic Agents
  • Depsipeptides
  • Reactive Oxygen Species