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

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.

Ouabain and Digoxin Activate the Proteasome and the Degradation of the ERα in Cells Modeling Primary and Metastatic Breast Cancer

“…Nonetheless, the present data also suggest caution should be applied in the use of these CGs in normal cells, and disclose the necessity to accurately choose concentrations of OU and Digo, and control their effects on the proteasome during the developmental phase of a CGs-based pharmacological treatment. Indeed, although we demonstrated that OU and Digo do not activate the proteasome in a non-transformed cell line, available data show that high proteasome activity relates to cancer development [ 56 , 57 ]. However, at the same time, our data strongly indicate that the OU and Digo ability to activate the proteasome is prospective for the treatment of ERα-expressing BCs.…”

Proteasomes and Several Aspects of Their Heterogeneity Relevant to Cancer

“…In addition, cancer stem cells are characterized by decreased proteasome activity and increased resistance to proteasome inhibitors (293), indicating that the improvement of inhibitor-based therapeutic approaches is necessary. Indeed, combinations of inhibitors with different molecules decreased the active dose required and increased inhibitor potency (283, 284). Different proteasome forms found in cancer cells are involved in the immune recognition of the tumor.…”

“…Along these lines, bortezomib is known for strong side-effects that limit its clinical use. To decrease the side-effects and increase the efficacy combinations of bortezomib with other molecules were proposed (283, 284). (B) Subunit specific inhibitors allowed targeting specific subsets of proteasomes and especially iP subunit-specific inhibitors are considered very useful against certain autoimmune disorders and inflammation-induced tumors (90, 91).…”

Bortezomib Dendrimer Prodrug‐Based Nanoparticle System

“…Bortezomib (BTZ) was the first proteasome inhibitor to be developed and is mainly used to treat hematologic tumors, such as multiple myeloma and small cell lymphoma . However, its usefulness for solid tumor therapy is limited owing to its poor stability and toxicity in vivo …”