APD-Containing Cyclolipodepsipeptides Target Mitochondrial Function in Hypoxic Cancer Cells

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.

Structure and function of the bacterial protein toxin phenomycin

“…Several recent examples have underscored the value of re-investigating such overlooked natural products. 1,2,3,4 We have a strong interest in structurally unusual peptidic natural products, 5,6,7 and therefore took notice of a series of reports on the compound phenomycin, which was first isolated in 1967 from Streptomyces fervens MA 564-Cl. 8 Phenomycin was found to possess antitumor activity in several different mouse models 9 but displayed no antibacterial activity.…”

Oxygen Starvation Unmasks a Killer

“…In this issue of Cell Chemical Biology, Jacobsen et al (2018) investigate the hypoxia selectivity of two cyclolipodepsipeptide natural products bearing a 4-amido-2,4-pentadienoate warhead. A switch in the cell death pathway under hypoxic conditions is observed, suggesting these electrophilic natural products have potential as a prodrug-free approach for treating hypoxic tumors.…”

“…In this issue of Cell Chemical Biology, the Poulsen lab explores the biological effects of two cyclic lipodepsipeptide natural products, Rakicidin A and BE-43547 ( Figure 1A), containing the electrophilic 4amido-2,4-pentadienoate (APD) warhead (Jacobsen et al, 2018). These compounds are used to probe the mechanism of yet another interesting phenotype, selective activity against hypoxic cells.…”

“…Seeking the molecular target(s) responsible for the sensitivity of hypoxic cells to APD lipodepsipeptides, Poulsen and colleagues (Jacobsen et al, 2018) developed an equipotent alkynyl probe and found that it labeled only three proteins (RTN4, RTN3, and CYB5B), each of which are associated with the mitochondria or ER. A further suggestion that these compounds operate via induction of mitochondrial and/or ER stress was gleaned from modulatory profiling, which implicated processes such as the ER stress response and the electron transport chain as critical for cytotoxic activity.…”

“…In their investigation of the APD lipodepsipeptides, Jacobsen et al (2018) suggest that the mechanism of cell death is different under different oxygen concentrations. By assessing annexin V binding and membrane permeabilization over time, the authors detected apoptotic progression under normoxia and a necrotic profile under hypoxia.…”