Abstract
Doxorubicin is one of the most effective chemotherapy drugs used against solid tumors in the treatment of several cancer types. Two different mechanisms, (i) intercalation of doxorubicin into DNA and inhibition of topoisomerase II leading to changes in chromatin structure, (ii) generation of free radicals and oxidative damage to biomolecules, have been proposed to explain the mode of action of this drug in cancer cells. A genome-wide integrative systems biology approach used in the present study to investigate the long-term effect of doxorubicin in Saccharomyces cerevisiae cells indicated the up-regulation of genes involved in response to oxidative stress as well as in Rad53 checkpoint sensing and signaling pathway. Modular analysis of the active sub-network has also revealed the induction of the genes significantly associated with nucleosome assembly/disassembly and DNA repair in response to doxorubicin. Furthermore, an extensive re-wiring of the metabolism was observed. In addition to glycolysis, and sulfate assimilation, several pathways related to ribosome biogenesis/translation, amino acid biosynthesis, nucleotide biosynthesis, de novo IMP biosynthesis and one-carbon metabolism were significantly repressed. Pentose phosphate pathway, MAPK signaling pathway biological processes associated with meiosis and sporulation were found to be induced in response to long-term exposure to doxorubicin in yeast cells.
Highlights
Doxorubicin, a natural anthracycline antibiotic, is one of the most effective chemotherapy drugs used against solid tumors in the treatment of several cancer types
Genome-wide transcriptomic response of yeast cells to the long-term presence of doxorubicin was analysed in the samples collected at the mid-exponential phase growth and integrated with the flux-balance analysis, followed by protein-protein interaction network in order to identify the long-term effect of the drug on living cells
The cultures grown in the absence or presence of doxorubicin in bioreactors were characterized for their uptake/secretion rates during the mid-exponential phase
Summary
Doxorubicin, a natural anthracycline antibiotic, is one of the most effective chemotherapy drugs used against solid tumors in the treatment of several cancer types. The analysis of genome-wide transcriptional response of yeast cells to long-term exposure to doxorubicin revealed that 1279 genes were differentially and significantly (a fold change greater than 1.5 and p value < 0.05) expressed when compared to control (Supplementary Table S4).
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