Metabolic targeting of cancer cells via the methylglyoxal detoxification systems

项目摘要/摘要 癌细胞的快速增殖通常是由于血糖的显著升高而引起的 消费。糖酵解flUX持续升高的结果是 甲基乙二醛(MG)等活性羰基物种。镁可形成晚期糖基化终末- 含有氨基酸、核酸和类脂的产品(AGEs)。DNA时代是特别的 之所以感兴趣，是因为它是糖代谢失调和 基因组不稳定。为了防止AGEs的形成，细胞部署谷胱甘肽- 依赖乙二酸酶1/2(Glo1/2)途径。Glo1在乳腺和前列腺中过度表达 肿瘤，并一直与不良预后相关。另外，BRCA1/2缺陷乳房， 卵巢癌和转移性前列腺癌正在临床上用抑制剂进行ff治疗 聚腺苷二磷酸核糖聚合酶(PARP)。在这里，我们建议研究Glo1的抑制作用 使用谷胱甘肽类似物，S-对溴苄基谷胱甘肽环戊二酯[p- BrBzGSH(CP)2]。一种新的稳定同位素稀释液相色谱串联质谱 光谱(SID-LC/MS/MS)方法将用于定量Glo1中的DNA年龄、CEdG 抑制剂治疗的癌细胞。我们的长期目标是看看我们是否可以利用Glo1来瞄准 缺乏靶向治疗的侵袭性糖酵解肿瘤。我们认为，对ff的选择性抑制 镁脱毒fi阳离子途径通过抑制Glo1或醛酮还原酶(Akr)将导致 CEdG及其下游突变和单链断裂的形成与增强细胞 死亡。(目的1)确定Glo1抑制在乳腺、前列腺、卵巢、卵巢和其他组织中的生物学效应。 和胰腺癌细胞。(目标2)询问Glo1抑制与Glo1抑制的协同作用 抑制DNA修复途径。在实现这些特定fic++目标方面的进展将有助于 建立将新的代谢靶点与PARP抑制剂配对的策略 选择性地杀死DNA修复能力减弱的糖酵解癌细胞。我们确实预料到 可能存在对Glo1抑制的代偿反应，我们知道Aldo-keto NADPH依赖的氧化还原酶超家族，可使MG解毒。 缺乏Glo1活动。我们也意识到谷胱甘肽的潜在过度表达。 在ff抑制Glo1的情况下可能会做出反应的生物合成途径。这项建议 将致力于阐明一种潜在的针对糖酵解肿瘤的新策略 其中没有靶向治疗，如三阴性乳腺癌和转移性乳腺癌 耐阉割的前列腺癌。

PROJECT SUMMARY/ABSTRACT The rapid proliferation of cancer cells is often fueled by a significant elevation in glucose consumption. A consequence of sustained elevation in glycolytic flux is the generation of reactive carbonyl species such as methylglyoxal (MG). MG can form advanced glycation end- products (AGEs) with amino acids, nucleic acids and lipids. The DNA AGE is of particular interest because it serves as a molecular link between dysregulated glucose metabolism and genome instability. In order to prevent the formation of AGEs, cells deploy the glutathione- dependent Glyoxalase 1/2 (Glo1/2) pathway. Glo1 is over-expressed in breast and prostate tumors and has been correlated with poor prognosis. Separately, BRCA1/2 defective breast, ovarian and metastatic prostate cancers are being treated effectively in the clinic with inhibitors of poly(ADP-ribose) polymerase (PARP). Here, we propose to investigate the inhibition of Glo1 using a glutathione analogue, S-p-bromobenzyl glutathione cyclopentyl diester [p- BrBzGSH(Cp)2]. A novel stable isotope dilution liquid chromatography tandem mass spectrometry (SID-LC/MS/MS) method will be used to quantify the DNA AGE, CEdG in Glo1 inhibitor treated cancer cells. Our long-term goal is to see if we can leverage Glo1 to target aggressive glycolytic tumors that lack targeted therapy. We propose that effective inhibition of MG detoxification pathways via Glo1 or aldo-keto reductase (AKR) inhibition will lead to the formation of CEdG and downstream mutations and single strand breaks and potentiate cell death. (Aim 1) To determine the biological effects of Glo1 inhibition in breast, prostate, ovarian, and pancreatic cancer cells. (Aim 2) To interrogate the synergy of Glo1 inhibition with the inhibition of DNA repair pathways. Progress towards these Specific Aims will contribute towards establishing a strategy of pairing a novel metabolic target with a PARP inhibitor to selectively kill glycolytic cancer cells with diminished DNA repair capacity. We do anticipate that there may be compensatory responses to Glo1 inhibition, we are aware of the aldo-keto reductase superfamily of NADPH-dependent oxido-reductases that may detoxify MG in the absence of Glo1 activity. We are also aware of the potential over-expression of the glutathione biosynthesis pathway that may respond in the event of effective Glo1 inhibition. This proposal will work towards illuminating a potential novel strategy for targeting glycolytic tumors for which there are no targeted therapy such as triple negative breast cancer and metastatic castration-resistant prostate cancer.