Apoptosis
Programmed cell death — a controlled process by which cells self-destruct when damaged or no longer needed. Proteasome inhibitors such as bortezomib and carfilzomib treat cancer by disrupting protein recycling, which triggers apoptosis in malignant cells.
Technical Context
Apoptosis proceeds through two main pathways: the intrinsic (mitochondrial) pathway, triggered by intracellular stress signals that release cytochrome c from mitochondria, activating caspase-9 and then effector caspases (caspase-3, -6, -7); and the extrinsic (death receptor) pathway, triggered by extracellular death ligands (TNF, FasL) activating caspase-8. Proteasome inhibitors (bortezomib, carfilzomib) trigger apoptosis primarily through the intrinsic pathway: proteasome inhibition causes accumulation of pro-apoptotic proteins (BH3-only proteins, p53) and misfolded proteins that trigger ER stress → unfolded protein response → caspase activation. Cancer cells are particularly sensitive because their high protein synthesis rate generates more proteotoxic stress. Apoptosis is morphologically distinct from necrosis — cells shrink, fragment, and are cleanly phagocytosed.