The biologically active metal-based compounds are of interest in both prevention and treatment of cancer. Metal-containing complexes are essential for the normal biochemical processes, and due to their reactivity, imbalance in the metal concentration is linked to the development of diverse malignancy. Several proteasome inhibitors contain metal complexes. Bortezomib (a boron complex) is the first successfully used therapeutic proteasome inhibitor in multiple myeloma (MM). However, major clinical limitations of the drug are the severe side effects caused by the inhibition of proteasomal and non-proteasomal activity in normal cells. Here we analyze the associations between individual metals and proteasome activity.
The study was performed on MM cell lines MM.1S and L363. Chymotrypsin–like (CT-like) proteasome activity is the primary measure of the degradation potential of the proteasome. In order to determine how metals are linked to proteasome activity, we expose MM cells to bortezomib or 5-amino-8-hydroxyquinoline dihydrochloride (5AHQ) proteasome inhibitors. The CT-like activities of β5 and β5i subunit were measured and evaluated based on a cumulative inhibition of β5 and β5i CT-like sites. Metal content analysis of MM.1S and L363 cells was performed by total reflection X-ray fluorescence spectrometer.
The metal content analysis demonstrated rigorous imbalances for calcium, phosphorus and potassium, moderate to no imbalances for iron and zinc accompanied by 65% MM.1S (54% L363) reduction of CT-like activity under bortezomib. However, under 5AHQ treatment, a decrease in the concentration of phosphorus and potassium was accompanied by minor to no change of iron and zinc levels and an increase of calcium. As metals may positively correlate or be antagonistic to one another, we evaluated the correlations between metals and proteasome activity.
Overall, our analysis suggests that the modulation of metal interactions specific to the proteasome activity is a strategy worth exploring to improve the efficacy of proteasome inhibition therapies.
Clinical trial identification
Legal entity responsible for the study
Wilhelm Sander Foundation.
All authors have declared no conflicts of interest.