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.
Highlights
Proteasomes, multicatalytic proteases, regulate cellular processes as well as cell proteome by the production of biologically active peptides and degradation of growth factors, receptors, signal-pathway components, transcription factors and other proteins [1,2,3]
The menadione sodium bisulfite (MSB) doses for antitumor compositions were determined by comparing the cytotoxic effect of MSB against malignant cells
We suggested that the synergetic effect of MSB and bortezomib on proteasome activity may be related to the process of bortezomib penetration into proteasome proteolytic chamber
Summary
Proteasomes, multicatalytic proteases, regulate cellular processes as well as cell proteome by the production of biologically active peptides and degradation of growth factors, receptors, signal-pathway components, transcription factors and other proteins [1,2,3]. In different animal and human malignant tumors, proteasome expression and chymotrypsin-like (ChTL) activity are enhanced relative to normal tissues [4,5,6,7,8]. The period of tumor regression coincided with the essential decrease in proteasome expression and ChTL-activity [9]. These facts indicate that tumor growth is highly dependent on the functional activity of proteasomes. Proteasomes are a promising target for antitumor drugs
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