Human multiple myeloma cells are sensitized to topoisomerase II inhibitors by CRM1 inhibition.
Human multiple myeloma cells are sensitized to topoisomerase II inhibitors by CRM1 inhibition.
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DOI：
10.1158/0008-5472.can-09-0484
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发表时间：
2009-09-01
期刊：
影响因子：
11.2
通讯作者：
Sullivan DM
中科院分区：
文献类型：
--
作者：
Turner JG;Marchion DC;Dawson JL;Emmons MF;Hazlehurst LA;Washausen P;Sullivan DM
Topoisomerase IIα (topo IIα) is exported from the nucleus of human myeloma cells by a CRM1-dependent mechanism at cellular densities similar to those found in patient bone marrow. When topo IIα is trafficked to the cytoplasm, it is not in contact with the DNA; thus topo IIα inhibitors are unable to induce DNA-cleavable complexes and cell death. Using a CRM1 inhibitor or a CRM1-specific small interfering RNA (siRNA), we were able to block nuclear export of topo IIα as shown by immunofluorescence microscopy. Human myeloma cell lines and patient myeloma cells isolated from bone marrow were treated with a CRM1 inhibitor or CRM1-specific siRNA and exposed to doxorubicin or etoposide (VP-16) at high cell densities. CRM1-treated cell lines or myeloma patient cells were fourfold more sensitive to topo II poisons, as determined by activated caspase assay. Normal cells were not significantly affected by CRM1-topo II combination treatment. Cell death was correlated with increased DNA double-strand breaks as shown by the comet assay. Band depletion assays of CRM1 inhibitor-exposed myeloma cells demonstrated increased topo IIα covalently bound to DNA. Topo IIα knockdown by a topo IIα-specific siRNA abrogated the CRM1-topo II therapy synergistic effect. These results suggest that blocking topo IIα nuclear export sensitizes myeloma cells to topo II inhibitors. This method of sensitizing myeloma cells suggests a new therapeutic approach to multiple myeloma.
