药理学专题-肿瘤细胞的代谢改变与抗肿瘤药物靶点的发现-邢美春 - 副本

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
Molecular Mechanisms of Cancer-Specific Metabolic Reprogramming
As a result of oncogenic gain-of-function events (pink) or the loss of tumor suppressors (green) affecting the PI3K/Akt/mTOR/HIF axis and/or inactivation of the p53 system, a stereotyped pattern of metabolic changes is induced, leading to cancer-associated alterations in metabolism.
The regulation of glucose metabolism in cancer cells
Warburg Effect
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. Miran Jang et al. Cancer cell metabolism: implications for therapeutic targets. Experimental & Molecular Medicine (2013) Oct 4;45:e45
THE CHANGES IN METABOLISM IN TUMOR AND THE FINDING OF NEW TARGETS
ABOUT METABOLIC ALTERATION OF CANCER CELL
higher proliferative rates
Metabolic activities in cancer cells are dramatically fast.
Direct targets consist of the metabolic enzymes themselves.
Indirect targets include signaling pathways that are activated or repressed in tumors, resulting in aberrant metabolic control.
Oncogenes and metabolism
Oncogenesis generally proceeds via the progressive acquisition of genetic and epigenetic alterations that together influence various cellular processes, including metabolic pathways. Such alterations, which generally involve either the inactivation of oncosuppressor genes or the hyperactivation of oncogenes, not only allow for malignant transformation but also support the survival of established tumours.
more specific inhibitors of this enzyme are important in treating glutamine-dependent tumors
Daniel A.Tennant et.al,Targeting metabolic transformation for cancer therapy. Nature, 10 267-277(2010)
3.Targeting amino acid metabolism several uses in பைடு நூலகம்he tumor cell
a substrate for protein synthesis non-essential amino acids (through transamination) replenish TCA cycle metabolite levels an essential starting point for nucleotide biosynthesis
have been used as chemotherapeutic agents for several years
inhibits the proliferation of tumor cells and promotes their differentiation；but were found to be toxic or raised an immune reaction
2.Targeting glycolysis
Agents used in combination with glycolysis inhibitors include both chemotherapy and radiotherapy do not seem to have as significant an effect on tumour growth as monotherapy But can resensitize tumors to other chemotherapeutic agents (such as paclitaxel)
Warburg effect
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.
1.Targeting nucleotide biosynthesis
Used as chemotherapeutic agents for several years target the final stages in the nucleotide synthetic pathway lack of tumour specificity few new agents in the clinic that directly target this pathway directed towards the pathways that supply intermediates to be used in nucleotide biosynthesis(PPP,TCA)
It is possible that the nucleotide building blocks necessary for normal proliferating cells can be supplied by the exogenous pool of nutrients, such as nucleosides. But owing to poor vascularization and the high proliferative burden of cancer cells, tumors might rely more on endogenous synthesis from glucose and glutamine Blocking early stages of nucleotide biosynthesis such as ribose-5phosphate (R5P) production could provide a better therapeutic window than that shown by previous antimetabolic therapies.