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.
The article presents an analysis of the intellectual property market in the field of enhanced oil recovery (EOR) methods. The search retrospectively covers the period from 2010 to 2020. Russia, China, and the United States are the leading countries in enhanced oil recovery methods. Canada, Germany, and Saudi Arabia also have a high level of patent activity compared with other countries. Semantic and statistical analysis of the obtained sample of documents made it possible to highlight the areas of intensive patenting, high competitiveness, as well as mainstream methods of enhanced oil recovery. The analysis of the leading companies’ patent portfolios revealed the similarities and differences in their structure. Tatneft, ConocoPhillips Co., Sinopec, and PetroChina Co. are actively patenting in the field of thermal enhanced oil recovery, which has been identified as the mainstream. BASF SE is focused on the production of chemicals, including chemicals for oil production. The Saudi Arabian Oil Company produces light oil using waterflooding and physicochemical methods. Software dominates the patent collection sector in the EORs of Gazpromneft STC and Lukoil.
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