An Endoplasmic Reticulum Specific Pro-amplifier of Reactive Oxygen Species in Cancer Cells

0550039 - ÚEB 2022 RIV DE eng J - Journal Article
Xu, H. G. - Schikora, A. - Šíša, Miroslav - Daum, S. - Klemt, I. - Janko, C. - Alexiou, C. - Bila, G. - Bilyy, R. - Gong, W. - Schmitt, M. - Sellner, L. - Mokhir, A.
An Endoplasmic Reticulum Specific Pro-amplifier of Reactive Oxygen Species in Cancer Cells.
Angewandte Chemie - International Edition. Roč. 60, č. 20 (2021), s. 11158-11162. ISSN 1433-7851. E-ISSN 1521-3773
Institutional support: RVO:61389030
Keywords : aminoferrocene * cancer * endoplasmic reticulum * prodrugs * reactive oxygen species
OECD category: Cell biology
Impact factor: 16.823, year: 2021
Method of publishing: Open access
http://doi.org/10.1002/anie.202100054

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.
Permanent Link: http://hdl.handle.net/11104/0326132