Inhibition of Mitochondrial Respiration by Amino‐Functionalized Gold Nanoparticles in Acute Myeloid Leukemia Cells

Abstract

In recent years, nanomaterials emerged as versatile tools for biomedical applications. Due to their special physicochemical characteristics, many different types of nanomaterials are under investigation for diagnostic as well as therapeutic purposes. We have previously shown the intrinsic cytotoxic activity of amino‐functionalized polystyrene nanoparticles towards acute myeloid leukemia cells. Here, we developed biocompatible gold nanoparticles with amino‐functionalization and investigated their mechanism of cellular toxicity.Acute myeloid leukemia (AML) is characterized by the proliferation and accumulation of mostly undifferentiated myeloid progenitor cells. In comparison to other leukemias, AML is a disease of the elderly with a mean age at diagnosis of 68 years. Due to severe side effects of the standard therapy, elderly AML patients often receive only palliative care, which results in profoundly reduced survival rates in older patients. Even though, a range of molecular changes in AML has already been investigated in detail, only few therapeutic agents have been approved. One possible explanation for the limited efficacy of targeted agents in AML might be the high level of genetic heterogeneity in myeloid leukemia.For a long time, glycolysis has been considered the major pathway of energy production in cancer cells, also known as the Warburg effect. Recently, however, oxidative phosphorylation emerged as a crucial metabolic pathway for the survival and proliferation of leukemia cells. The high dependence of acute myeloid leukemia cells on oxidative phosphorylation suggests the possibility to target the mitochondrial respiratory chain for antileukemic efficacy.Here, we performed high resolution respirometry using an Oroboros oxygraph and show the enhanced respiratory activity of THP‐1 leukemia cells compared to healthy peripheral mononuclear cells. Furthermore, chromogenic complex activity assays employed to study the effect of gold nanoparticles on respiratory complex activities of isolated mitochondria demonstrated that the amino‐functionalized gold nanoparticles, but not the carboxy‐functionalized control particles, inhibit mitochondrial complex activities. We could further show that such direct inhibitory effect on mitochondrial complex activities also impairs mitochondrial respiration in intact THP‐1 cells. Inhibition of mitochondrial respiration further led to depolarization of the mitochondrial membrane, depletion of ATP, and cell death of THP‐1 cells and primary AML blasts.Hence, our findings confirm the high dependence of AML cells on oxidative phosphorylation. On that basis, our amino‐functionalized gold nanoparticles represent novel nanotherapeutics for a broad application in AML therapy, specifically targeting and inhibiting the sensitive energy production pathway in AML cells.Support or Funding InformationThis work was supported by the Volkswagen Foundation.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.