Interaction of Bortezomib with Cell Membranes Regulates Its Toxicity and Resistance to Therapy

Abstract

Bortezomib (BTZ) is a potent proteasome inhibitor currently being used to treat multiple myeloma. However, its high toxicity and resistance to therapy severely limit the treatment outcomes. Drug–membrane interactions have a crucial role in drugs’ behavior in vivo, affecting their bioavailability and pharmacological activity. Additionally, drugs’ toxicity often occurs due to their effects on the cell membranes. Therefore, studying BTZ’s interactions with cell membranes may explain the limitations of its therapy. Due to the cell membranes’ complexity, lipid vesicles were proposed here as biomembrane models, focusing on the membrane’s main constituents. Two models with distinct composition and complexity were used, one composed of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and the other containing DMPC, cholesterol (Chol), and sphingomyelin (SM). BTZ’s interactions with the models were evaluated regarding the drugs’ lipophilicity, preferential location, and effects on the membrane’s physical state. The studies were conducted at different pH values (7.4 and 6.5) to mimic the normal blood circulation and the intestinal environment, respectively. BTZ revealed a high affinity for the membranes, which proved to be dependent on the drug-ionization state and the membrane complexity. Furthermore, BTZ’s interactions with the cell membranes was proven to induce changes in the membrane fluidity. This may be associated with its resistance to therapy, since the activity of efflux transmembrane proteins is dependent on the membrane’s fluidity.