Targeted and Functional Genomics Approaches to the Mechanism of Action of Lagunamide D, a Mitochondrial Cytotoxin from Marine Cyanobacteria

Biochem Pharmacol. 2023 May 16:115608. doi: 10.1016/j.bcp.2023.115608. Online ahead of print.ABSTRACTLagunamide D, a cyanobacterial cyclodepsipeptide, exhibits potent antiproliferative activity against HCT116 colorectal cancer cells (IC50 5.1 nM), used as a model system to probe the mechanism of action. Measurements of metabolic activity, mitochondrial membrane potential, caspase 3/7 activity and cell viability indicate the rapid action of lagunamide D on mitochondrial function and downstream cytotoxic effects in HCT116 cells. Lagunamide D preferentially targets the G1 cell cycle population and arrests cells in G2/M phase at high concentration (32 nM). RNA-Transcriptomics and subsequent Ingenuity Pathway Analysis identified networks related to mitochondrial functions. Lagunamide D induced mitochondrial network redistribution at 10 nM, suggesting a mechanism shared with the structurally related aurilide family, previously reported to target mitochondrial prohibitin 1 (PHB1). Knockdown and chemical inhibition of ATP1A1 sensitized the cells to lagunamide D, as also known for aurilide B. We interrogated potential mechanisms behind this synergistic effect between lagunamide D and ATP1A1 knockdown by using pharmacological inhibitors and extended the functional analysis to a global level by performing a chemogenomic screen with a siRNA library targeting the human druggable genome, revealing targets that modulate susceptibility to lagunamide D. In addition to mitochondrial targets, t...
Source: Biochemical Pharmacology - Category: Drugs & Pharmacology Authors: Source Type: research