药理学专题-肿瘤细胞的代谢改变跟抗肿瘤医学药物靶点的发现-邢美春 - 副本.pptxVIP

The changes in metabolism in tumor and the finding of new targets;higher proliferative rates Metabolic activities in cancer cells are dramatically fast. more nutrient hungry and excrete more waste products resulting in a build-up of metabolites inside the cell and the formation of a more hostile environment outside the cell In order to divide, a cell needs to both increase its size and replicate its DNA — processes that are hugely metabolically demanding and which require large quantities of proteins, lipids and nucleotides, as well as energy in the form of ATP ;Drivers (A and B). The metabolic derangements in cancer cells may arise either from the selection of cells that have adapted to the tumor microenvironment or from aberrant signaling due to oncogene activation. Advantages (C–E). The altered metabolism of cancer cells is likely to imbue them with several proliferative and survival advantages, Potential Liabilities (F and G). This altered metabolism, however, may also confer several vulnerabilities on cancer cells. ;When glucose enters the cell through a glucose transporter, it is phosphorylated by HK to glucose-6-phosphate, which is further metabolized by glycolysis to pyruvate in the cytosol. Under aerobic conditions, normal cells use pyruvate dehydrogenase (PDH) to convert most pyruvate to acetyl-CoA. The acetyl-CoA is then oxidized via the TCA cycle, providing sources of ATP synthesis. In contrast, the metabolic pathways of glucose utilization in cancer are changed from ATP generation by oxidative phosphorylation to ATP generation through glycolysis. Also, for cell proliferation to occur, cancer cells require the synthesis of new macromolecules (for example, nucleic acids, lipids, proteins). Key enzymes that may be promising targets for cancer therapy are highlighted in red. TCA enzymes that are known to be mutated in cancer are shown in purple: IDH2, SDH, and FH.;Daniel A. Tennant et.al, Targeting metabolic transformation for cancer therapy. Nature, 10 2