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This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Hazlehurst, L. A. Articles by Dalton, W. S. Search for Related Content PubMed PubMed Citation Articles by Hazlehurst, L. A. Articles by Dalton, W. S. Related Collections Neoplasia Apoptosis Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 September 2001, Vol. 98, No. 6, pp. 1897-1903 NEOPLASIA Reduction in drug-induced DNA double-strand breaks associated with 1 integrin-mediated adhesion correlates with drug resistance in U937 cells Lori A. Hazlehurst, Nikola Valkov, Lee Wisner, Jonathan A. Storey, David Boulware, Daniel M. Sullivan, and William S. Dalton From the Department of Interdisciplinary Oncology and Clinical Investigations Program and the Biostatistical Department, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL. We previously showed that adhesion of myeloma cells to fibronectin (FN) by means of 1 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 1 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 1 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 II protein levels. Confocal studies showed changes in the nuclear localization of topo II; however, alterations in the nuclear-to-cytoplasmic ratio of topo II in FN-adhered cells were not significantly different. Furthermore, after a high level of salt extraction of nuclear proteins, higher levels of topo II-associated DNA binding were observed in FN-adhered cells than in cells in suspension. Together, these data suggest that topo II is more tightly bound to the nucleus of FN-adhered cells. Thus, FN adhesion by means of 1 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 II. © 2001 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: K. H. Shain, D. N. Yarde, M. B. Meads, M. Huang, R. Jove, L. A. Hazlehurst, and W. S. Dalton {beta}1 Integrin Adhesion Enhances IL-6-Mediated STAT3 Signaling in Myeloma Cells: Implications for Microenvironment Influence on Tumor Survival and Proliferation Cancer Res., February 1, 2009; 69(3): 1009 - 1015. [Abstract] [Full Text] [PDF] P. S. Becker, K. J. Kopecky, A. N. Wilks, S. Chien, J. M. Harlan, C. L. Willman, S. H. Petersdorf, D. L. Stirewalt, T. Papayannopoulou, and F. R. Appelbaum Very late antigen-4 function of myeloblasts correlates with improved overall survival for patients with acute myeloid leukemia Blood, January 22, 2009; 113(4): 866 - 874. [Abstract] [Full Text] [PDF] M. B. Meads, L. A. Hazlehurst, and W. S. Dalton The Bone Marrow Microenvironment as a Tumor Sanctuary and Contributor to Drug Resistance Clin. Cancer Res., May 1, 2008; 14(9): 2519 - 2526. [Abstract] [Full Text] [PDF] L. E. Perez, N. Parquet, K. Shain, R. Nimmanapalli, M. Alsina, C. Anasetti, and W. Dalton Bone Marrow Stroma Confers Resistance to Apo2 Ligand/TRAIL in Multiple Myeloma in Part by Regulating c-FLIP J. Immunol., February 1, 2008; 180(3): 1545 - 1555. [Abstract] [Full Text] [PDF] M. Kobune, H. Chiba, J. Kato, K. Kato, K. Nakamura, Y. Kawano, K. Takada, R. Takimoto, T. Takayama, H. Hamada, et al. Wnt3/RhoA/ROCK signaling pathway is involved in adhesion-mediated drug resistance of multiple myeloma in an autocrine mechanism Mol. Cancer Ther., June 1, 2007; 6(6): 1774 - 1784. [Abstract] [Full Text] [PDF] R. Yoshimi, S. Yamaji, A. Suzuki, W. Mishima, M. Okamura, T. Obana, C. Matsuda, Y. Miwa, S. Ohno, and Y. Ishigatsubo The {gamma}-Parvin-Integrin-Linked Kinase Complex Is Critically Involved in Leukocyte-Substrate Interaction J. Immunol., March 15, 2006; 176(6): 3611 - 3624. [Abstract] [Full Text] [PDF] L. A. Hazlehurst, R. F. Argilagos, M. Emmons, D. Boulware, C. A. Beam, D. M. Sullivan, and W. S. Dalton Cell Adhesion to Fibronectin (CAM-DR) Influences Acquired Mitoxantrone Resistance in U937 Cells Cancer Res., February 15, 2006; 66(4): 2338 - 2345. [Abstract] [Full Text] [PDF] J. L. Rose, H. Huang, S. F. Wray, and D. G. Hoyt Integrin Engagement Increases Histone H3 Acetylation and Reduces Histone H1 Association with DNA in Murine Lung Endothelial Cells Mol. Pharmacol., August 1, 2005; 68(2): 439 - 446. [Abstract] [Full Text] [PDF] J. G. Turner, R. Engel, J. A. Derderian, R. Jove, and D. M. Sullivan Human topoisomerase II{alpha} nuclear export is mediated by two CRM-1-dependent nuclear export signals J. Cell Sci., June 15, 2004; 117(14): 3061 - 3071. [Abstract] [Full Text] [PDF] L. A. Hazlehurst, S. A. Enkemann, C. A. Beam, R. F. Argilagos, J. Painter, K. H. Shain, S. Saporta, D. Boulware, L. Moscinski, M. Alsina, et al. Genotypic and Phenotypic Comparisons of de Novo and Acquired Melphalan Resistance in an Isogenic Multiple Myeloma Cell Line Model Cancer Res., November 15, 2003; 63(22): 7900 - 7906. [Abstract] [Full Text] [PDF] N. Mitsiades, C. S. Mitsiades, P. G. Richardson, V. Poulaki, Y.-T. Tai, D. Chauhan, G. Fanourakis, X. Gu, C. Bailey, M. Joseph, et al. The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications Blood, March 15, 2003; 101(6): 2377 - 2380. [Abstract] [Full Text] [PDF] K. H. Shain, T. H. Landowski, and W. S. Dalton Adhesion-Mediated Intracellular Redistribution of c-Fas-Associated Death Domain-Like IL-1-Converting Enzyme-Like Inhibitory Protein-Long Confers Resistance to CD95-Induced Apoptosis in Hematopoietic Cancer Cell Lines J. Immunol., March 1, 2002; 168(5): 2544 - 2553. [Abstract] [Full Text] [PDF] M. M. Oshiro, T. H. Landowski, R. Catlett-Falcone, L. A. Hazlehurst, M. Huang, R. Jove, and W. S. Dalton Inhibition of JAK Kinase Activity Enhances Fas-mediated Apoptosis but Reduces Cytotoxic Activity of Topoisomerase II Inhibitors in U266 Myeloma Cells Clin. Cancer Res., December 1, 2001; 7(12): 4262 - 4271. [Abstract] [Full Text] [PDF] K. H. Shain and W. S. Dalton Cell Adhesion Is a Key Determinant in de Novo Multidrug Resistance (MDR): New Targets for the Prevention of Acquired MDR Mol. Cancer Ther., November 1, 2001; 1(1): 69 - 78. [Abstract] [Full Text] [PDF]

	Copyright © 2001 by American Society of Hematology         Online ISSN: 1528-0020