bortezomib

Bortezomib is a reversible inhibitor of the 26S proteasome, a complex responsible for degrading ubiquitin-tagged intracellular proteins, including regulators of the cell cycle (p21, p27) and NF-κB inhibitor (IκB). By blocking proteasomal degradation, bortezomib causes accumulation of pro-apoptotic proteins and prevents NF-κB activation (which normally promotes cell survival and proliferation), leading to cell cycle arrest and apoptosis preferentially in rapidly dividing malignant plasma cells. It is FDA-approved for multiple myeloma (often in combination with dexamethasone and other agents like lenalidomide - the 'VRd' regimen) and mantle cell lymphoma. Administered via IV or subcutaneous injection. Major adverse effects include peripheral neuropathy (dose-limiting, often sensory), thrombocytopenia, GI disturbances (nausea, diarrhea), fatigue, and reactivation of herpes zoster (prophylaxis with acyclovir is often given). Peripheral neuropathy is a key board-testable toxicity, distinguishing it from other myeloma drugs like lenalidomide (associated with venous thromboembolism) and thalidomide (teratogenicity, neuropathy, thrombosis). Mechanistically, understanding the ubiquitin-proteasome pathway is important: proteins tagged with ubiquitin are normally degraded by the proteasome, and bortezomib's inhibition of this pathway is central to its antineoplastic effect. This drug exemplifies targeted therapy exploiting cancer cell dependence on protein homeostasis, since malignant plasma cells produce large amounts of immunoglobulin and are particularly sensitive to proteasome inhibition due to accumulation of misfolded proteins and subsequent unfolded protein response-induced apoptosis.