Signal transduction pathways and transcriptional mechanisms as targets for prevention of emergence of multidrug resistance in human cancer cells

Pleiotropic resistance of tumor cells to treatment remains one of the major obstacles for successful cure of cancer patients. Tumor cells may acquire multidrug resistance (MDR) in the course of exposure to various compounds that are used in modern anticancer therapy, including cytotoxic drugs and differentiating agents. Therefore, the recurrence of the disease after the initial treatment may be associated with establishment of secondary MDR in the residual tumor. This phenotype is frequently mediated by P-glycoprotein, an ATP-dependent transmembrane pump capable of effluxing numerous compounds out of the cell. In hum ans, P-glycoprotein is encoded by the MDR1 gene. Rapid increase of the steady-state level of the MDR1 mRNA in response to stress stimuli is the mechanism of acquisition of P-glycoprotein-mediated MDR in cancer cells. Thus, up-regulation of the MDR1 gene is regarded as part of cellular stress response. This review shows that block of mechanisms that regulate the MDR1 overexpression can prevent the emergence of MDR in tumor cells that expressed null-to-low levels of MDR1 mRNA or P-glycoprotein prior to treatment. In particular, the MDR1 activation can be abrogated by targeting cytoplasmic pathways of signal transduction as well as by interfering with transcriptional up-regulation.