Identification of molecular targets associated to gemcitabine and rebeccamycin analogues resistance using Saccharomyces cerevisiae as model cell

Abstract

Gemcitabine and rebeccamycin are molecules which present antitumoral activity. The first one is currently used as single agent in pancreatic cancer treatment or in combination with other drugs in several types of cancer, while analogues of the second have been tested in phase II clinical trials in breast and lung cancers. Gemcitabine is an analogue of deoxycytidine that inhibits DNA synthesis, and also presents inhibitory effects over several proteins, such as deoxycytidine monophosphate deaminase, topoisomerase I and ribonucleotide reductase. Rebeccamycin and its analogues include DNA intercalant molecules and topoisomerase I inhibitors. Some of these analogues can also inhibit the activity of kinases, such as Chk1, which is important for the G2/M cell cycle checkpoint. The mechanisms related to the resistance to these drugs are poorly understood and some have been suggested; even though, there is no consensus about the cellular pathways involved. The aim of this project is to identify molecular targets associated to the resistance to these drugs, and also analyze the redox state of cells treated with these antitumorals, using Saccharomyces cerevisiae as a model cell. We are going to start screening in a mutant yeast collection in order to identify genes which may play a role in the resistance to gemcitabine and rebeccamycin analogues. After this, we are going to analyze the gene expression and target-proteins activity related to this response. Using yeast as a eukaryotic model cell may be useful to understand complex processes such as drug resistance, apoptosis and cell cycle, all of them directly related to cancer.