University of Florida Research Foundation, Incorporated

H. Lee Moffitt Cancer Center and Research Institute, Inc.

Joel G Turner

David A Ostrov

Thomas Cardon Rowe

Daniel M Sullivan

Topoisomerase II alpha (topo II&#x3b1;) 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 II&#x3b1; is unique, making it a potential target for small molecule inhibitors. Small molecules NES inhibitors were identified, which inhibited binding of topo II&#x3b1; to the export receptor CRM1. Inhibition was specific to topo II&#x3b1; as p53 trafficking was unaffected along with topo II&#x3b1; protein expression and function (decatenation). These topo II&#x3b1;-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.

Drug targets to overcome de novo drug-resistance in multiple myeloma

A method of treating cancer in a subject comprising the step of administering to the subject in need thereof an effective amount of a combination of a compound that binds a nuclear export signal (NES inhibitor) on topoisomerase II&#x3b1; and a topoisomerase inhibitor. Twenty small molecule inhibitors (SMI) that bind to the two nuclear export sequences (NES) topo II&#x3b1; have been identified from the NCI database using computer-generated molecular modeling. These SMI will improve the effectiveness of topo II directed therapeutics, particularly in the treatment of diseases such as multiple myeloma (MM). In vitro apoptosis assays indicate that these drugs may be effective as single agents or in combination with currently used cancer drugs that target topo II.

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Joel G Turner