Signal Transduction Pathways and Transcriptional Mechanisms as Targets for Prevention of Emergence of Multidrug Resistance in Human Cancer Cells

Author: Shtil A.A.

Source: Current Drug Targets, Volume 2, Number 1, March 2001 , pp. 57-77(21)

Publisher: Bentham Science Publishers

Abstract:

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 humans, 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.

Keywords: Multidrug resistance MDR; P-glycoprotein; MDR1 gene; kDa-glycoprotein; Protein Kinase PKC; Plasma Membrane-Active Agents; Nuclear factor Kappa B; Isoform; Isoform; Polyamides; Single gene targeting

Language: English

Document Type: Review article

DOI: http://dx.doi.org/10.2174/1389450013348957

Publication date: 2001-03-01

• Current Drug Targets aims to cover the latest and most outstanding developments on the medicinal chemistry and pharmacology of molecular drug targets e.g. disease specific proteins, receptors, enzymes, genes. Each issue of the journal will be devoted to a single timely topic, with series of in-depth reviews, written by leaders in the field, covering a range of current topics on drug targets. These issues will be organized and led by a guest editor who is a recognized expert in the overall topic. As the discovery, identification, characterisation and validation of novel human drug targets for drug discovery continues to grow; this journal will be essential reading for all pharmaceutical scientists involved in drug discovery and development.

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