DNA Topoisomerase and Proteasome (Topo/Proteasome)

Topoisomerases and the proteasome are distinct but functionally interconnected therapeutic targets primarily utilized in the treatment of hematological and solid malignancies. Topoisomerases are enzymes that regulate DNA supercoiling and tangling by creating transient breaks in the DNA phosphodiester backbone, which is essential for replication and transcription (Pommier, 2013, Nature Reviews Cancer). The proteasome is a sophisticated multi-catalytic complex responsible for the degradation of polyubiquitinated proteins, thereby maintaining cellular protein homeostasis and regulating the cell cycle (Tanaka, 2009, Proceedings of the Japan Academy). In clinical practice, topoisomerase inhibitors like irinotecan and etoposide are used to induce catastrophic DNA damage, while proteasome inhibitors such as bortezomib are used to prevent the degradation of pro-apoptotic factors and tumor suppressors (Moreau et al., 2012, Blood). Emerging research suggests that dual inhibition of these pathways can synergistically enhance tumor cell death by preventing the repair of topoisomerase-induced DNA lesions through the stabilization of inhibitory proteins (Zhang et al., 2018, European Journal of Medicinal Chemistry). This combination approach is particularly relevant in overcoming resistance mechanisms in refractory cancers such as multiple myeloma and certain leukemias (Gandolfi et al., 2017, Cancer Discovery).

Other names

DNA Topoisomerase26S ProteasomeMulticatalytic Endopeptidase Complex20S ProteasomeTopo ITopo IIProteasome complex

Topoisomerase inhibitors act by stabilizing the transient DNA-enzyme complexes (cleavage complexes), preventing DNA ligation and leading to lethal double-strand breaks during replication. Proteasome inhibitors reversibly or irreversibly bind to the catalytic sites of the 20S core particle, blocking the degradation of regulatory proteins like IκB, leading to cell cycle arrest and apoptosis.