title: Investigation on metabolism of cisplatin resistant ovarian cancer using a genome scale metabolic model and microarray data.
abstract: OBJECTIVE
  Many cancer cells show significant resistance to drugs that kill drug sensitive cancer cells and non-tumor cells and such resistance might be a consequence of the difference in metabolism. Therefore, studying the metabolism of drug resistant cancer cells and comparison with drug sensitive and normal cell lines is the objective of this research.
  
  
  METHODS
  Metabolism of cisplatin resistant and sensitive A2780 epithelial ovarian cancer cells and normal ovarian epithelium has been studied using a generic human genome-scale metabolic model and transcription data.
  
  
  RESULTS
  The results demonstrate that the most different metabolisms belong to resistant and normal models, and the different reactions are involved in various metabolic pathways. However, large portion of distinct reactions are related to extracellular transport for three cell lines. Capability of metabolic models to secrete lactate was investigated to find the origin of Warburg effect. Computational results introduced SLC25A10 gene, which encodes mitochondrial dicarboxylate transporter involved in exchanging of small metabolites across the mitochondrial membrane that may play key role in high growing capacity of sensitive and resistant cancer cells. The metabolic models were also used to find single and combinatorial targets that reduce the cancer cells growth. Effect of proposed target genes on growth and oxidative phosphorylation of normal cells were determined to estimate drug side-effects.
  
  
  CONCLUSIONS
  The deletion results showed that although the cisplatin did not cause resistant cancer cells death, but it shifts the cancer cells to a more vulnerable metabolism.
authors.affiliation: Biotechnology Group, Department of Chemical Engineering, Tarbiat Modares University, Tehran, Iran ; Drug Design and Bioinformatics Group, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.
authors.forename: Ehsan
authors.initials: E
authors.lastname: Motamedian
authors.affiliation: Drug Design and Bioinformatics Group, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran ; Eastern Mediterranean Health Genomics and Biotechnology Network (EMGEN), Tehran, Iran.
authors.forename: Ghazaleh
authors.initials: G
authors.lastname: Ghavami
authors.affiliation: Drug Design and Bioinformatics Group, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.
authors.forename: Soroush
authors.initials: S
authors.lastname: Sardari
keywords: Cisplatin resistance; Drug target; Lactate; Metabolism; Microarray; Warburg effect