Product Description

Bortezomib is a reversible and selective proteasome inhibitor that effectively inhibits the 20S proteasome (Ki = 0.6 nM) by targeting threonine residues. It exhibits antitumor activity, inhibits NF-κB, disrupts cell cycle progression, and induces apoptosis. Bortezomib is approved for the treatment of relapsed/refractory multiple myeloma and mantle cell lymphoma in patients who have received at least one prior therapy.

Screeningbio‘s SW620/Bortezomib resistance cell line generated by exposing to increasing concentration of drug for certain period of time. After stable acquire resistance, cells were harvested and characterized for drug resistance by 7 days proliferation assay.

Data

Target Background

Bortezomib (Velcade) is a first‑in‑class proteasome inhibitor that reversibly binds to the catalytic site of the 26S proteasome, blocking the degradation of ubiquitinated proteins. This leads to accumulation of pro‑apoptotic factors, disruption of intracellular protein homeostasis, activation of the unfolded protein response (UPR), and ultimately cell cycle arrest and apoptosis in rapidly dividing cancer cells. It is widely used in the treatment of multiple myeloma and mantle cell lymphoma. However, the development of drug resistance remains a major challenge limiting its long‑term efficacy.

Mechanistically, bortezomib resistance arises through multiple cellular adaptations. Mutations or altered expression of proteasome subunits (e.g., PSMB5, the primary binding site) reduce drug binding affinity, while upregulation of efflux transporters such as P‑glycoprotein (MDR1/ABCB1) decreases intracellular drug accumulation. Additionally, activation of survival pathways—including PI3K/Akt, MAPK, and NF‑κB signaling (paradoxically, as bortezomib normally inhibits NF‑κB)—promotes anti‑apoptotic responses. Changes in the unfolded protein response (UPR) toward adaptive branches (e.g., IRE1‑XBP1 or ATF4 signaling) and enhanced autophagy or increased expression of anti‑apoptotic Bcl‑2 family proteins also contribute to reduced drug sensitivity. Epithelial–mesenchymal transition (EMT) and alterations in the tumor microenvironment (e.g., bone marrow stromal cell‑mediated protection) further promote resistance.

Understanding these mechanisms is critical for designing strategies to overcome resistance, such as combining bortezomib with second‑generation proteasome inhibitors (e.g., carfilzomib), efflux transporter inhibitors, targeting downstream survival pathways, or employing patient‑derived resistant cell models to guide personalized therapy development.