Reduction in drug-induced DNA double-strand breaks associated with beta1 integrin-mediated adhesion correlates with drug resistance in U937 cells.
We previously showed that adhesion of myeloma cells to fibronectin ( FN) by means of beta1 integrins causes resistance to certain cytotoxic drugs. The study described here found that adhesion of U937 human histiocytic lymphoma cells to FN provides a survival advantage with respect to damage induced by the topoisomerase (topo) II inhibitors mitoxantrone, doxorubicin, and etoposide. Apoptosis induced by a topo II inhibitor is thought to be initiated by DNA damage. The neutral comet assay was used to determine whether initial drug-induced DNA damage correlated with cellular-adhesion-mediated drug resistance. Cellular adhesion by means of beta1 integrins resulted in a 40% to 60% reduction in mitoxantrone- and etoposide-induced DNA double-strand breaks. When the mechanisms regulating the initial drug-induced DNA damage were examined, a beta1 integrin-mediated reduction in drug-induced DNA double-strand breaks was found to correlate with reduced topo II activity and decreased salt-extractable nuclear topo IIbeta protein levels. Confocal studies showed changes in the nuclear localization of topo IIbeta; however, alterations in the nuclear-to-cytoplasmic ratio of topo IIbeta in FN-adhered cells were not significantly different. Furthermore, after a high level of salt extraction of nuclear proteins, higher levels of topo IIbeta-associated DNA binding were observed in FN-adhered cells than in cells in suspension. Together, these data suggest that topo IIbeta is more tightly bound to the nucleus of FN-adhered cells. Thus, FN adhesion by means of beta1 integrins appears to protect U937 cells from initial drug-induced DNA damage by reducing topo II activity secondarily to alterations in the nuclear distribution of topo IIbeta.[1]References
- Reduction in drug-induced DNA double-strand breaks associated with beta1 integrin-mediated adhesion correlates with drug resistance in U937 cells. Hazlehurst, L.A., Valkov, N., Wisner, L., Storey, J.A., Boulware, D., Sullivan, D.M., Dalton, W.S. Blood (2001) [Pubmed]
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