Yeast as a Biosensor of Detoxification: A Tool for Identifying New Compounds that Revert Multidrug Resistance

Carmen      Martín-Cordero; Angeles      Sanchez-Pico; Antonio   J.   Leon-Gonzalez; Antonio   J.   Perez-Pulido; Rafael   R.   Daga

Abstract

During tumour progression, cells accumulate secondary mutations and/or chromosomal aberrations that generate genetic diversity within the tumour cell population. This may result in the acquisition of new properties that increase tumour malignancy, such as invasiveness or resistance to chemotherapy. One of the important mechanisms of chemotherapy resistance is overexpression or biochemical activation of ABC family transporters. ABC transporters remove antitumour drugs from the cell, reducing their intracellular concentration and producing resistance against a wide range of chemically unrelated drugs, known as multidrug resistant phenotype (MDR). During recent decades, much effort has been devoted to the isolation of compounds able to inhibit the activity of these transporters. However, few such compounds have reached clinical practice and MDR remains a serious complication in cancer therapy. In an innovative approach to finding new ABC inhibitors, we propose using fission yeast Schizosaccharomyces pombe as a biosensor of detoxification that would enable cost-efficient screening of natural compounds and chemical libraries for molecules that revert the MDR phenotype. Existing fission yeast tools provide genetic, biochemical and cell biological analysis, thereby facilitating identification of drug targets. Putative inhibitors and modulators of ABC transporters could be used in combination with chemotherapeutic drugs for the treatment of multidrug resistant tumours.

Keywords: ABC transporter, ABC inhibitor/modulator/chemosensitizer, cancer chemotherapy, drug screen, efflux pump, multidrug resistance, natural compounds, Schizosaccharomyces pombe.