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.
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.
Iran J Basic Med Sci. 2015 Mar;18(3):267-76.
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.
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.
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.
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.
许多癌细胞对杀死药物敏感癌细胞和非肿瘤细胞的药物表现出明显的耐药性，这种耐药性可能是代谢差异的结果。因此，研究耐药性癌细胞的代谢，并与药物敏感和正常细胞系进行比较，是本研究的目的。
使用通用的人类基因组规模代谢模型和转录数据研究顺铂耐药和敏感 A2780 上皮卵巢癌细胞和正常卵巢上皮细胞的代谢。
结果表明，最不同的代谢属于耐药和正常模型，不同的反应涉及各种代谢途径。然而，三个细胞系中大部分不同的反应与细胞外运输有关。为了寻找沃伯格效应的起源，研究了代谢模型分泌乳酸的能力。计算结果介绍了 SLC25A10 基因，该基因编码参与线粒体膜小代谢物交换的线粒体二羧酸转运体，可能在敏感和耐药癌细胞的高生长能力中发挥关键作用。还使用代谢模型寻找单一和组合靶点来降低癌细胞的生长。为了估计药物的副作用，确定了对正常细胞生长和氧化磷酸化有影响的靶基因。
删除结果表明，尽管顺铂不会导致耐药癌细胞死亡，但它会使癌细胞转向更脆弱的代谢。
