Targeted Magnetic Intra-Lysosomal Hyperthermia produces lysosomal reactive oxygen species and causes Caspase-1 dependent cell death

Abstract

Therapeutic strategies using drugs which cause Lysosomal Cell Death have been proposed for eradication of resistant cancer cells. In this context, nanotherapy based on Magnetic Intra-Lysosomal Hyperthermia (MILH) generated by magnetic nanoparticles (MNPs) that are grafted with ligands of receptors overexpressed in tumors appears to be a very promising therapeutic option. However, mechanisms whereby MILH induces cell death are still elusive. Herein, using Gastrin-grafted MNPs specifically delivered to lysosomes of tumor cells from different cancers, we provide evidences that MILH causes cell death through a non-apoptotic signaling pathway. The mechanism of cell death involves a local temperature elevation at the nanoparticle periphery which enhances the production of reactive oxygen species through the lysosomal Fenton reaction. Subsequently, MILH induces lipid peroxidation, lysosomal membrane permeabilization and leakage of lysosomal enzymes into the cytosol, including Cathepsin-B which activates Caspase-1 but not apoptotic Caspase-3. These data highlight the clear potential of MILH for the eradication of tumors overexpressing receptors.

Magnetic (Hyper)Thermia or Photothermia? Progressive Comparison of Iron Oxide and Gold Nanoparticles Heating in Water, in Cells, and In Vivo

“…One strategy consists of applying magnetic nanoparticles with aminosilane coating, which prevents nanoparticles from entering the cells (this strategy was used by MagForce AG, The Nanomedicine Company), whereas a second alternative comprises functionalization of magnetic nanoparticles with membrane ligands, which specifically target membrane receptors of a given cell type, with an induced cytotoxic response which does not involve global heating on the cellular level. [16b,33]…”

The Lysosomal Membrane Protein Lamp2 Alleviates Lysosomal Cell Death by Promoting Autophagic Flux in Ischemic Cardiomyocytes

“…The most common cell death pathway associated with lysosomes is called lysosomal cell death (LCD) (Gomez-Sintes et al, 2016;Gaidt et al, 2017;Mai et al, 2017). LCD is characterized by lysosomal membrane permeabilization (LMP) and mediated by the release of lysosomal cathepsins into the cytoplasm, which causes caspase-dependent and caspase-independent cell death (Windelborn and Lipton, 2008;Jiang et al, 2016;Clerc et al, 2018). To date, many pathogenic factors that induce LMP have been discovered, including ROS, lysosomotropic drugs, bacterial and viral products (de Duve, 2005;Huang et al, 2017;Malet et al, 2017).…”

Recent Advances in Subcellular Targeted Cancer Therapy Based on Functional Materials

“…Furthermore, a more in‐depth study was carried out to elucidate the cellular and molecular mechanism. Besides thermal effect, the magnetic intralysosomal hyperthermia could also enhance the production of ROS through lysosomal Fenton reaction, leading to the lipid peroxidation, LMP, lysosomal enzyme (e.g., Caspase‐1 and cathepsin B but not apoptotic Caspase‐3) leakage, and finally cell death . These studies highlight the clear potential of lysosome‐targeted thermal ablation of receptor‐overexpressed tumors and motivate researchers to discover more receptor targets for LMP‐mediated cell killing owing to the variation of receptors among different kinds of cancers.…”