NOVEL DRUG TARGETS TO OVERCOME DE NOVO DRUG-RESISTANCE IN MULTIPLE MYELOMA

摘要

Topoisomerase II alpha (topo IIa) is exported from the cell nucleus in human myeloma cells by a chromosome-maintenance protein-1 (CRM1)-dependent mechanism, resulting in topo II inhibitor resistance. The nuclear export signal (NES) of topo IIa is unique, making it a potential target for small molecule inhibitors. Small molecules NES inhibitors were identified, which inhibited binding of topo IIa to the export receptor CRM1. Inhibition was specific to topo IIa as p53 trafficking was unaffected along with topo IIa protein expression and function (decatenation). These topo IIa-specific nuclear export inhibitors may potentially lead to a new approach in circumventing drug resistance in multiple myeloma. The compounds provide a protocol for treating multiple myeloma or an oncogenic disease. Further, the topoisomerase II nuclear export signal inhibitor may be combined with a topoisomerase II inhibitor.