Lysosomal Destabilizing Drug Siramesine and the Dual Tyrosine Kinase Inhibitor Lapatinib Induce a Synergistic Ferroptosis through Reduced Heme Oxygenase-1 (HO-1) Levels.

Gloria E Villalpando-Rodriguez,Carmen Konzelman,Anna R Blankstein,Spencer B Gibson

doi:10.1155/2019/9561281

Gloria E Villalpando-Rodriguez, Carmen Konzelman + Show 2 more

Open Access

https://doi.org/10.1155/2019/9561281

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Abstract

Ferroptosis is an iron-dependent type of cell death distinct from apoptosis or necrosis characterized by accumulation of reactive oxygen species. The combination of siramesine, a lysosomotropic agent, and lapatinib, a dual tyrosine kinase inhibitor (TKI), synergistically induced cell death in breast cancer cells mediated by ferroptosis. In this study, we showed that this combination of siramesine and lapatinib induces synergistic cell death in glioma cell line U87 and lung adenocarcinoma cell line A549. This cell death was characterized by the increase in iron content, reactive oxygen species (ROS) production, and lipid peroxidation accumulation after 24 hours of treatment. Moreover, iron chelator DFO and ferrostatin-1, a ferroptosis inhibitor, significantly reduced cell death. The mechanism underlying the activation of the ferroptotic pathway involves lysosomal permeabilization and increase in reactive iron levels in these cells. In addition, the downregulation of heme oxygenase-1 (HO-1) protein occurred. Overexpression of HO-1 resulted in reduction of ROS and lipid peroxidation production and cell death. Furthermore, knocking down of HO-1 combined with siramesine treatment resulted in increased cell death. Finally, we found that the inhibition of the proteasome system rescued HO-1 expression levels. Our results suggest that the induction of ferroptosis by combining a lysosomotropic agent and a tyrosine kinase inhibitor is mediated by iron release from lysosomes and HO-1 degradation by the proteasome system.

Highlights

In cancer cells, the most common types of cell death such as apoptosis are often actively inhibited, contributing to the development of drug resistance
We first determine if siramesine alone was capable to induce cell death, for these A549 or U87 cells were treated with different concentrations of siramesine
Since previous studies showed that the combination of siramesine and lapatinib was capable to induce synergistic cell death in breast cancer cell lines, we tested different combinations of tyrosine kinase inhibitors (TKIs) and lysosomotropic agents

Summary

Introduction

The most common types of cell death such as apoptosis are often actively inhibited, contributing to the development of drug resistance. Ferroptosis is a cell death mechanism that is morphologically, biochemically, and genetically distinct from other types of cell death. It is characterized by the iron-dependent intracellular accumulation of reactive oxygen species (ROS) and lipid peroxidation products [2] [3]. Ferroptosis can be inhibited by preventing the accumulation of ROS from lipid peroxidation using ferrostatin-1 (Fer-1) or by binding free iron in the cell using chelators like deferoxamine (DFO) [4]

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