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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

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          Abstract

          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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          Most cited references 31

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          Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays

          A tetrazolium salt has been used to develop a quantitative colorimetric assay for mammalian cell survival and proliferation. The assay detects living, but not dead cells and the signal generated is dependent on the degree of activation of the cells. This method can therefore be used to measure cytotoxicity, proliferation or activation. The results can be read on a multiwell scanning spectrophotometer (ELISA reader) and show a high degree of precision. No washing steps are used in the assay. The main advantages of the colorimetric assay are its rapidity and precision, and the lack of any radioisotope. We have used the assay to measure proliferative lymphokines, mitogen stimulations and complement-mediated lysis.
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            Superoxide dismutase: improved assays and an assay applicable to acrylamide gels.

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              Superoxide dismutases.

               I Fridovich (1974)
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                Author and article information

                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                25 September 2018
                October 2018
                : 10
                : 10
                Affiliations
                [1 ]Laboratory of Biochemistry of Ontogenesis Processes, Koltzov Institute of Developmental Biology, Russian Academy of Sciences, 26 Vavilov Street, 119334 Moscow, Russia; tastakhova@ 123456bk.ru (T.M.A.); erokhov.p@ 123456gmail.com (P.A.E.); maria@ 123456actremed.ru (M.I.M.); chupikova@ 123456actremed.ru (N.I.C.); safarov@ 123456actremed.ru (R.R.S.)
                [2 ]Laboratory of Regulation of Intracellular Proteolysis, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov Street, 119991 Moscow, Russia; runkel@ 123456inbox.ru
                [3 ]Laboratory of Human Genes Structure and Functions, Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry of Russian Academy of Sciences, 16/10 Miklukho-Maklay Street, 117997 Moscow, Russia; sergeyakopov@ 123456mail.ru
                Author notes
                [* ]Correspondence: npsharova@ 123456bk.ru ; Tel.: +7-499-135-7674; Fax: +7-499-135-3322
                Article
                cancers-10-00351
                10.3390/cancers10100351
                6209890
                30257462
                © 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/).

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