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 Mia-pa-ca-2/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 chymotrypsin‑like active site of the 20S proteasome, blocking the degradation of ubiquitinated proteins and leading to accumulation of misfolded proteins, endoplasmic reticulum (ER) stress, and activation of intrinsic and extrinsic apoptotic pathways in rapidly dividing cancer cells. It is primarily 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 in both hematologic and solid malignancies.

Mechanistically, bortezomib resistance arises through multiple cellular adaptations. Mutations or altered expression of the proteasome β5 subunit (PSMB5) reduce drug binding affinity and proteasome inhibition, while upregulation of efflux transporters such as P‑glycoprotein (MDR1/ABCB1) decreases intracellular drug accumulation. Additionally, activation of survival pathways—including NF‑κB (paradoxically), PI3K/Akt, MAPK/ERK, and Hedgehog signaling—promotes anti‑apoptotic responses. Increased expression of aggresome‑associated autophagy (e.g., via HDAC6 and p62), upregulation of heat shock proteins (HSP27, HSP70, and HSP90), changes in anti‑apoptotic Bcl‑2 family proteins, and enhanced epithelial–mesenchymal transition (EMT) also contribute to reduced drug sensitivity.

Understanding these mechanisms is critical for designing strategies to overcome resistance, such as combination therapy with second‑generation proteasome inhibitors (e.g., carfilzomib or ixazomib), efflux transporter modulators, autophagy inhibitors (e.g., chloroquine), HSP90 inhibitors, or agents targeting compensatory pathways (e.g., PI3K/Akt or NF‑κB inhibitors), as well as employing patient‑derived resistant cell models to guide personalized therapy development.