Lee W-N P, Guo P, Lim S, Bassilian S, Lee S T, Boren J, Cascante M, Go V L W, Boros L G
Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, RB1, 1124 West Carson Street, Torrance, CA 90502, USA.
Br J Cancer. 2004 Dec 13;91(12):2094-100. doi: 10.1038/sj.bjc.6602243.
Inhibitors of glycogen breakdown regulate glucose homeostasis by limiting glucose production in diabetes. Here we demonstrate that restrained glycogen breakdown also inhibits cancer cell proliferation and induces apoptosis through limiting glucose oxidation, as well as nucleic acid and de novo fatty acid synthesis. Increasing doses (50-100 microM) of the glycogen phosphorylase inhibitor CP-320626 inhibited [1,2-(13)C(2)]glucose stable isotope substrate re-distribution among glycolysis, pentose and de novo fatty acid synthesis in MIA pancreatic adenocarcinoma cells. Limited oxidative pentose-phosphate synthesis, glucose contribution to acetyl CoA and de novo fatty acid synthesis closely correlated with decreased cell proliferation. The stable isotope-based dynamic metabolic profile of MIA cells indicated a significant dose-dependent decrease in macromolecule synthesis, which was detected at lower drug doses and before the appearance of apoptosis markers. Normal fibroblasts (CRL-1501) did not show morphological or metabolic signs of apoptosis likely due to their slow rate of growth and metabolic activity. This indicates that limiting carbon re-cycling and rapid substrate mobilisation from glycogen may be an effective and selective target site for new drug development in rapidly dividing cancer cells. In conclusion, pancreatic cancer cell growth arrest and death are closely associated with a characteristic decrease in glycogen breakdown and glucose carbon re-distribution towards RNA/DNA and fatty acids during CP-320626 treatment.
糖原分解抑制剂通过限制糖尿病患者的葡萄糖生成来调节葡萄糖稳态。在此，我们证明，抑制糖原分解还可通过限制葡萄糖氧化以及核酸和从头脂肪酸合成来抑制癌细胞增殖并诱导细胞凋亡。增加糖原磷酸化酶抑制剂CP - 320626的剂量（50 - 100微摩尔）可抑制MIA胰腺腺癌细胞中[1,2 - (13)C(2)]葡萄糖稳定同位素底物在糖酵解、戊糖和从头脂肪酸合成之间的重新分布。氧化戊糖磷酸合成受限、葡萄糖对乙酰辅酶A的贡献以及从头脂肪酸合成与细胞增殖减少密切相关。基于稳定同位素的MIA细胞动态代谢谱表明，大分子合成显著呈剂量依赖性下降，在较低药物剂量时即可检测到，且早于凋亡标志物出现之前。正常成纤维细胞（CRL - 1501）未表现出凋亡的形态学或代谢迹象，这可能是由于其生长速率和代谢活性较低。这表明限制碳循环以及从糖原快速动员底物可能是快速分裂癌细胞新药开发的有效且选择性的靶点。总之，在CP - 320626治疗期间，胰腺癌细胞生长停滞和死亡与糖原分解以及葡萄糖碳向RNA/DNA和脂肪酸的重新分布的特征性减少密切相关。
