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Role of the Raf Signal Transduction Cascade in the in Vitro Resistance to the Anticancer Drug Doxorubicin¹

Department of Microbiology and Immunology [C. R. W-O., J. M. D., P. M. N., O. A. S., L. S. S., R. A. F., P. J. R., J. A. M.] and Leo Jenkins Cancer Center [R. A. F., J. A. M.], Brody School of Medicine at East Carolina University, Greenville, North Carolina 27858; Escuela de Química y Farmacia, Facultad de Medicina [C. R. W-O.] and Departamento de Estadística, Facultad de Ciencias [C. F. H-R.], Universidad de Valparaíso, Valparaíso, Chile; Department of Biostatistics, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599 [C. F. H-R.]; Department of Cell Signaling, DNAX Research Institute of Molecular and Cellular Biology, Palo Alto, California 94304 [M. M.]

The precise molecular events involved in the development of drug resistance (DR) remain largely unknown. Raf is an intermediate in the signal transduction cascades initiated by growth factors. The hypothesis behind the following studies is that deregulated Raf-1 expression plays a role in the development of drug resistance. A positive correlation was observed between increased Raf-1 activity and increased values for IC₅₀ for doxorubicin in established cell lines. The National Cancer Institute/Adriamycin Resistant (NCI/ADR-RES) cell line exhibited both the highest Raf-1 activity and the highest IC₅₀ values for doxorubicin (Adriamycin). In contrast, the MCF-7 cell line exhibited both lower Raf activity and lower IC₅₀ values for doxorubicin. While MCF-7 cells transfected with either constitutively active Raf-1 or conditionally active Raf-1:AR demonstrated increased IC₅₀ values for doxorubicin and a reduced capacity to undergo apoptosis after doxorubicin treatment as compared with parental cell lines. Moreover, growth curves performed show that both the constitutively and conditionally active forms of Raf-1 do not increase growth as compared with the parental MCF-7 cell line. This is important because it implies that higher cell counts between Raf transfectants and the parental MCF-7 cell line are attributable to differences in DR, not growth rates. These observations suggest a role for the Raf-1 protooncogene in the regulation of DR.

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