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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MDPI AG
2018-09-01
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| Series: | Cancers |
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| Online Access: | http://www.mdpi.com/2072-6694/10/10/351 |
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| author | Tatiana M. Astakhova Alexey V. Morozov Pavel A. Erokhov Maria I. Mikhailovskaya Sergey B. Akopov Natalia I. Chupikova Ruslan R. Safarov Natalia P. Sharova |
| author_facet | Tatiana M. Astakhova Alexey V. Morozov Pavel A. Erokhov Maria I. Mikhailovskaya Sergey B. Akopov Natalia I. Chupikova Ruslan R. Safarov Natalia P. Sharova |
| author_sort | Tatiana M. Astakhova |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-12T08:06:23Z |
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| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T08:06:23Z |
| publishDate | 2018-09-01 |
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| series | Cancers |
| spelling | doaj.art-f1b7de935cfe4e7e8f22373d2bb0b3382023-09-02T19:32:06ZengMDPI AGCancers2072-66942018-09-01101035110.3390/cancers10100351cancers10100351Combined Effect of Bortezomib and Menadione Sodium Bisulfite on Proteasomes of Tumor Cells: The Dramatic Decrease of Bortezomib Toxicity in a Preclinical TrialTatiana M. Astakhova0Alexey V. Morozov1Pavel A. Erokhov2Maria I. Mikhailovskaya3Sergey B. Akopov4Natalia I. Chupikova5Ruslan R. Safarov6Natalia P. Sharova7Laboratory of Biochemistry of Ontogenesis Processes, Koltzov Institute of Developmental Biology, Russian Academy of Sciences, 26 Vavilov Street, 119334 Moscow, RussiaLaboratory of Regulation of Intracellular Proteolysis, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov Street, 119991 Moscow, RussiaLaboratory of Biochemistry of Ontogenesis Processes, Koltzov Institute of Developmental Biology, Russian Academy of Sciences, 26 Vavilov Street, 119334 Moscow, RussiaLaboratory of Biochemistry of Ontogenesis Processes, Koltzov Institute of Developmental Biology, Russian Academy of Sciences, 26 Vavilov Street, 119334 Moscow, RussiaLaboratory of Human Genes Structure and Functions, Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry of Russian Academy of Sciences, 16/10 Miklukho-Maklay Street, 117997 Moscow, RussiaLaboratory of Biochemistry of Ontogenesis Processes, Koltzov Institute of Developmental Biology, Russian Academy of Sciences, 26 Vavilov Street, 119334 Moscow, RussiaLaboratory of Biochemistry of Ontogenesis Processes, Koltzov Institute of Developmental Biology, Russian Academy of Sciences, 26 Vavilov Street, 119334 Moscow, RussiaLaboratory of Biochemistry of Ontogenesis Processes, Koltzov Institute of Developmental Biology, Russian Academy of Sciences, 26 Vavilov Street, 119334 Moscow, RussiaTumor 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.http://www.mdpi.com/2072-6694/10/10/351target and drug discoveryproteasome formsbortezomibmenadione sodium bisulfitehepatocellular carcinomamammary adenocarcinomaLewis lung carcinomaantitumor effect in vivoacute toxicity |
| spellingShingle | Tatiana M. Astakhova Alexey V. Morozov Pavel A. Erokhov Maria I. Mikhailovskaya Sergey B. Akopov Natalia I. Chupikova Ruslan R. Safarov Natalia P. Sharova Combined Effect of Bortezomib and Menadione Sodium Bisulfite on Proteasomes of Tumor Cells: The Dramatic Decrease of Bortezomib Toxicity in a Preclinical Trial Cancers target and drug discovery proteasome forms bortezomib menadione sodium bisulfite hepatocellular carcinoma mammary adenocarcinoma Lewis lung carcinoma antitumor effect in vivo acute toxicity |
| 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 | target and drug discovery proteasome forms bortezomib menadione sodium bisulfite hepatocellular carcinoma mammary adenocarcinoma Lewis lung carcinoma antitumor effect in vivo acute toxicity |
| url | http://www.mdpi.com/2072-6694/10/10/351 |
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