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Combined Effect of Bortezomib and Menadione Sodium Bisulfite on Proteasomes of Tumor Cells: The Dramatic Decrease of Bortezomib Toxicity in a Preclinical Trial

Tumor growth is associated with elevated proteasome expression and activity. This makes proteasomes a promising target for antitumor drugs. Current antitumor drugs such as bortezomib that inhibit proteasome activity have significant side effects. The purpose of the present study was to develop effec...

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Autores principales: Astakhova, Tatiana M., Morozov, Alexey V., Erokhov, Pavel A., Mikhailovskaya, Maria I., Akopov, Sergey B., Chupikova, Natalia I., Safarov, Ruslan R., Sharova, Natalia P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6209890/
https://www.ncbi.nlm.nih.gov/pubmed/30257462
http://dx.doi.org/10.3390/cancers10100351
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author Astakhova, Tatiana M.
Morozov, Alexey V.
Erokhov, Pavel A.
Mikhailovskaya, Maria I.
Akopov, Sergey B.
Chupikova, Natalia I.
Safarov, Ruslan R.
Sharova, Natalia P.
author_facet Astakhova, Tatiana M.
Morozov, Alexey V.
Erokhov, Pavel A.
Mikhailovskaya, Maria I.
Akopov, Sergey B.
Chupikova, Natalia I.
Safarov, Ruslan R.
Sharova, Natalia P.
author_sort Astakhova, Tatiana M.
collection PubMed
description Tumor growth is associated with elevated proteasome expression and activity. This makes proteasomes a promising target for antitumor drugs. Current antitumor drugs such as bortezomib that inhibit proteasome activity have significant side effects. The purpose of the present study was to develop effective low-toxic antitumor compositions with combined effects on proteasomes. For compositions, we used bortezomib in amounts four and ten times lower than its clinical dose, and chose menadione sodium bisulfite (MSB) as the second component. MSB is known to promote oxidation of NADH, generate superoxide radicals, and as a result damage proteasome function in cells that ensure the relevance of MSB use for the composition development. The proteasome pool was investigated by the original native gel electrophoresis method, proteasome chymotrypsin-like activity—by Suc-LLVY-AMC-hydrolysis. For the compositions, we detected 10 and 20 μM MSB doses showing stronger proteasome-suppressing and cytotoxic in cellulo effects on malignant cells than on normal ones. MSB indirectly suppressed 26S-proteasome activity in cellulo, but not in vitro. At the same time, MSB together with bortezomib displayed synergetic action on the activity of all proteasome forms in vitro as well as synergetic antitumor effects in cellulo. These findings determine the properties of the developed compositions in vivo: antitumor efficiency, higher (against hepatocellular carcinoma and mammary adenocarcinoma) or comparable to bortezomib (against Lewis lung carcinoma), and drastically reduced toxicity (LD50) relative to bortezomib. Thus, the developed compositions represent a novel generation of bortezomib-based anticancer drugs combining high efficiency, low general toxicity, and a potentially expanded range of target tumors.
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spelling pubmed-62098902018-11-02 Combined Effect of Bortezomib and Menadione Sodium Bisulfite on Proteasomes of Tumor Cells: The Dramatic Decrease of Bortezomib Toxicity in a Preclinical Trial Astakhova, Tatiana M. Morozov, Alexey V. Erokhov, Pavel A. Mikhailovskaya, Maria I. Akopov, Sergey B. Chupikova, Natalia I. Safarov, Ruslan R. Sharova, Natalia P. Cancers (Basel) Article Tumor growth is associated with elevated proteasome expression and activity. This makes proteasomes a promising target for antitumor drugs. Current antitumor drugs such as bortezomib that inhibit proteasome activity have significant side effects. The purpose of the present study was to develop effective low-toxic antitumor compositions with combined effects on proteasomes. For compositions, we used bortezomib in amounts four and ten times lower than its clinical dose, and chose menadione sodium bisulfite (MSB) as the second component. MSB is known to promote oxidation of NADH, generate superoxide radicals, and as a result damage proteasome function in cells that ensure the relevance of MSB use for the composition development. The proteasome pool was investigated by the original native gel electrophoresis method, proteasome chymotrypsin-like activity—by Suc-LLVY-AMC-hydrolysis. For the compositions, we detected 10 and 20 μM MSB doses showing stronger proteasome-suppressing and cytotoxic in cellulo effects on malignant cells than on normal ones. MSB indirectly suppressed 26S-proteasome activity in cellulo, but not in vitro. At the same time, MSB together with bortezomib displayed synergetic action on the activity of all proteasome forms in vitro as well as synergetic antitumor effects in cellulo. These findings determine the properties of the developed compositions in vivo: antitumor efficiency, higher (against hepatocellular carcinoma and mammary adenocarcinoma) or comparable to bortezomib (against Lewis lung carcinoma), and drastically reduced toxicity (LD50) relative to bortezomib. Thus, the developed compositions represent a novel generation of bortezomib-based anticancer drugs combining high efficiency, low general toxicity, and a potentially expanded range of target tumors. MDPI 2018-09-25 /pmc/articles/PMC6209890/ /pubmed/30257462 http://dx.doi.org/10.3390/cancers10100351 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Astakhova, Tatiana M.
Morozov, Alexey V.
Erokhov, Pavel A.
Mikhailovskaya, Maria I.
Akopov, Sergey B.
Chupikova, Natalia I.
Safarov, Ruslan R.
Sharova, Natalia P.
Combined Effect of Bortezomib and Menadione Sodium Bisulfite on Proteasomes of Tumor Cells: The Dramatic Decrease of Bortezomib Toxicity in a Preclinical Trial
title Combined Effect of Bortezomib and Menadione Sodium Bisulfite on Proteasomes of Tumor Cells: The Dramatic Decrease of Bortezomib Toxicity in a Preclinical Trial
title_full Combined Effect of Bortezomib and Menadione Sodium Bisulfite on Proteasomes of Tumor Cells: The Dramatic Decrease of Bortezomib Toxicity in a Preclinical Trial
title_fullStr Combined Effect of Bortezomib and Menadione Sodium Bisulfite on Proteasomes of Tumor Cells: The Dramatic Decrease of Bortezomib Toxicity in a Preclinical Trial
title_full_unstemmed Combined Effect of Bortezomib and Menadione Sodium Bisulfite on Proteasomes of Tumor Cells: The Dramatic Decrease of Bortezomib Toxicity in a Preclinical Trial
title_short Combined Effect of Bortezomib and Menadione Sodium Bisulfite on Proteasomes of Tumor Cells: The Dramatic Decrease of Bortezomib Toxicity in a Preclinical Trial
title_sort combined effect of bortezomib and menadione sodium bisulfite on proteasomes of tumor cells: the dramatic decrease of bortezomib toxicity in a preclinical trial
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6209890/
https://www.ncbi.nlm.nih.gov/pubmed/30257462
http://dx.doi.org/10.3390/cancers10100351
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