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Cell Adhesion to Fibronectin (CAM-DR) Influences Acquired Mitoxantrone Resistance in U937 Cells

¹ Department of Interdisciplinary Oncology and Experimental Therapeutics Program and ² Biostatistics Core Facility, H. Lee Moffitt Cancer Center and Research Institute at the University of South Florida, Tampa, Florida

Requests for reprints: William Dalton, Department of Interdisciplinary Oncology and Experimental Therapeutics Program, H. Lee Moffitt Cancer Center and Research Institute at the University of South Florida, 12902 Magnolia Drive, Tampa, FL 33613. Phone: 813-903-6807; E-mail: dalton{at}moffitt.usf.edu.

Cell adhesion to fibronectin is known to confer a temporally related cell adhesion–mediated drug resistance (CAM-DR). However, it is unknown whether cell adhesion during drug selection influences the more permanent form of acquired drug resistance. To examine this question, we compared the acquisition of mitoxantrone resistance in U937 cells adhered to fibronectin versus cells selected in a traditional suspension culture. Our data show that acquired drug resistance levels of resistance to mitoxantrone are 2- to 3-fold greater for cells adhered to fibronectin compared with cells in suspension culture. We also compared mechanism(s) of resistance associated with drug selection in suspension versus fibronectin-adherent cultures. Drug resistance in both suspension and fibronectin-adhered cultures correlated with reduced drug-induced DNA damage and diminished topoisomerase II levels and activity; however, mechanisms regulating topoisomerase II levels differed depending on culture conditions. In suspension cultures, a reduction in topoisomerase IIß levels was detected at both RNA and protein levels. Furthermore, the decreased expression of topoisomerase IIß mRNA levels correlated with decreased expression of NF-YA. In contrast, in spite of no changes in NF-YA or topoisomerase IIß RNA expression, topoisomerase IIß protein levels were decreased in fibronectin-adherent, drug-resistant cells. In addition, topoisomerase II protein levels (but not RNA levels) were reduced in drug resistance cells selected on fibronectin; however, no change in topoisomerase II was observed in cells selected with mitoxantrone in suspension culture. Taken together, our results suggest that the development of drug resistance models must consider interactions with the microenvironment to identify clinically relevant targets and mechanisms associated with acquired drug resistance. (Cancer Res 2006; 66(4): 2338-45)

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