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

摘要

Topoisomerase II alpha (topo IIalpha) 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 IIalpha is unique, making it a potential target for small molecule inhibitors. Small molecules NES inhibitors were identified, which inhibited binding of topo IIalpha to the export receptor CRM1. Inhibition was specific to topo IIalpha as p53 trafficking was unaffected along with topo IIalpha protein expression and function (decatenation). These topo IIalpha-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.