Metabolic targeting of cancer cells via the methylglyoxal detoxification systems

通过甲基乙二醛解毒系统代谢靶向癌细胞

• 批准号: 10078955
• 负责人: Daniel Tamae
• 金额: $ 14.5万
• 依托单位: CALIFORNIA STATE UNIVERSITY NORTHRIDGE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-05 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10078955
• 关键词: AKR1C1; Acetaminophen; Advanced Glycosylation End Products; Affect; Amino Acids; Anabolism; Area; Awareness; BRCA1 Mutation; BRCA1 gene; Biological; Biological Assay; Breast; Breast Cancer cell line; Bromides; CRISPR/Cas technology; Cancer cell line; Cell Death; Cell Extracts; Cell Line; Cell Proliferation; Cells; Cellular Metabolic Process; Clinic; Clinical; Consumption; Cysteine; DNA; DNA Damage; DNA Repair; DNA Repair Enzymes; DNA Repair Inhibition; DNA Repair Pathway; Deoxyuridine; Dose; Drug Metabolic Detoxication; Enzymes; Event; Generations; Genomic Instability; Glucose; Glutathione; Glutathione Disulfide; Glycolysis; Goals; Lactoylglutathione Lyase; Lead; Ligase; Link; Lipids; Liquid Chromatography; Literature; Malignant Neoplasms; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Mammary Neoplasms; Metabolic; Metabolism; Metastatic Prostate Cancer; Methods; Modeling; Molecular; Mutation; NADP; Naproxen; Nucleic Acids; Nucleotides; Ovarian; Oxidoreductase; Pathway interactions; Phosphorylation; Poly(ADP-ribose) Polymerases; Positioning Attribute; Prognosis; Prostatic Neoplasms; Proxy; Pyruvaldehyde; Quantitative Reverse Transcriptase PCR; RNA; Reduced Glutathione; Small Interfering RNA; System; Testing; Time; Transcript; Trioses; Western Blotting; Work; brca gene; buthionine; cancer cell; cancer type; castration resistant prostate cancer; cell killing; glucose metabolism; glutathione analog; glutathione synthase; glycation; inhibitor/antagonist; inorganic phosphate; interest; knock-down; liquid chromatography mass spectrometry; malignant breast neoplasm; member; novel; novel strategies; novel therapeutic intervention; overexpression; pancreatic cancer cells; prevent; response; small molecule inhibitor; stable isotope; synergism; tandem mass spectrometry; targeted treatment; tolrestat; triple-negative invasive breast carcinoma; tumor

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.

项目总结/摘要 癌细胞的快速增殖通常是由葡萄糖的显著升高所推动的。 消费糖酵解β-射线持续升高的结果是产生 反应性羰基物质如甲基乙二醛（MG）。MG可形成晚期糖基化终末- AGEs与氨基酸、核酸和脂质的结合。DNA年龄是一个特殊的 因为它是葡萄糖代谢失调和 基因组不稳定性为了防止AGEs的形成，细胞会释放谷胱甘肽- Glycoproteinase 1/2（Glo 1/2）途径。Glo 1在乳腺和前列腺中过表达 肿瘤，并与预后不良相关。另外，BRCA 1/2缺陷乳房， 卵巢癌和转移性前列腺癌在临床上用抑制剂有效地治疗 聚腺苷二磷酸核糖聚合酶（PARP）。在这里，我们建议研究Glo 1的抑制 使用谷胱甘肽类似物S-对溴苄基谷胱甘肽环戊基二酯[p- BrBzGSH（Cp）2]。一种新型稳定同位素稀释液相色谱串联质谱 将使用SID-LC/MS/MS方法定量Glo 1中的DNA AGE、CEdG 抑制剂处理的癌细胞。我们的长期目标是看看我们是否可以利用Glo 1来瞄准 缺乏靶向治疗的侵袭性糖酵解肿瘤。我们认为，有效抑制 通过Glo 1或醛酮还原酶（AKR）抑制的MG脱毒途径将导致 CEdG和下游突变的形成和单链断裂， 死亡(Aim 1）确定Glo 1抑制在乳腺、前列腺、卵巢、 和胰腺癌细胞。(Aim 2）为了询问Glol抑制与Glol抑制的协同作用， 抑制DNA修复途径。实现这些具体目标将有助于 旨在建立将新的代谢靶标与PARP抑制剂配对的策略， 选择性地杀死具有降低的DNA修复能力的糖酵解癌细胞。我们预计 可能存在对Glo 1抑制的代偿反应，我们知道醛酮 还原酶超家族的NADPH依赖性氧化还原酶，可以解毒MG在 没有Glo 1活性。我们也意识到谷胱甘肽的潜在过度表达 在Glo 1有效抑制的情况下，可能响应的生物合成途径。这项建议 将致力于阐明一种潜在的靶向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， 去势抵抗性前列腺癌