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An Endoplasmic Reticulum Specific Pro-amplifier of Reactive Oxygen Species in Cancer Cells.
- Source :
-
Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2021 May 10; Vol. 60 (20), pp. 11158-11162. Date of Electronic Publication: 2021 Apr 08. - Publication Year :
- 2021
-
Abstract
- 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.<br /> (© 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)
- Subjects :
- Animals
Antineoplastic Agents chemistry
Endoplasmic Reticulum metabolism
Humans
Lymphoma metabolism
Mice
Mice, Inbred C57BL
Molecular Structure
Neoplasms, Experimental drug therapy
Neoplasms, Experimental metabolism
Prodrugs chemistry
Antineoplastic Agents pharmacology
Endoplasmic Reticulum drug effects
Lymphoma drug therapy
Prodrugs pharmacology
Reactive Oxygen Species metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1521-3773
- Volume :
- 60
- Issue :
- 20
- Database :
- MEDLINE
- Journal :
- Angewandte Chemie (International ed. in English)
- Publication Type :
- Academic Journal
- Accession number :
- 33656236
- Full Text :
- https://doi.org/10.1002/anie.202100054