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An Endoplasmic Reticulum Specific Pro‐amplifier of Reactive Oxygen Species in Cancer Cells
Author(s) -
Xu HongGui,
Schikora Margot,
Sisa Miroslav,
Daum Steffen,
Klemt Insa,
Janko Christina,
Alexiou Christoph,
Bila Galyna,
Bilyy Rostyslav,
Gong Wenjie,
Schmitt Michael,
Sellner Leopold,
Mokhir Andriy
Publication year - 2021
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.202100054
Subject(s) - endoplasmic reticulum , unfolded protein response , reactive oxygen species , prodrug , cancer cell , chemistry , bortezomib , carfilzomib , microbiology and biotechnology , proteasome , biochemistry , cancer , cancer research , proteasome inhibitor , biology , multiple myeloma , medicine , immunology
The folding and export of proteins and hydrolysis of unfolded proteins are disbalanced in the endoplasmic reticulum (ER) of cancer cells, leading to so‐called ER stress. Agents further augmenting this effect are used as anticancer drugs including clinically approved proteasome inhibitors bortezomib and carfilzomib. However, these drugs can affect normal cells, which also rely strongly on ER functions, leading, for example, to accumulation of reactive oxygen species (ROS). To address this problem, we have developed ER‐targeted prodrugs activated only in cancer cells in the presence of elevated ROS amounts. These compounds are conjugates of cholic acid with N‐alkylaminoferrocene‐based prodrugs. We confirmed their accumulation in the ER of cancer cells, their anticancer efficacy, and cancer cell specificity. These prodrugs induce ER stress, attenuate mitochondrial membrane potential, and generate mitochondrial ROS leading to cell death via necrosis. We also demonstrated that the new prodrugs are activated in vivo in Nemeth‐Kellner lymphoma (NK/Ly) murine model.