The chemical biology of pharmacological ascorbate in cancer treatment

药理学抗坏血酸在癌症治疗中的化学生物学

基本信息

批准号：
8658412
负责人：
Garry R Buettner
金额：
$ 30.39万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-07 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8658412
关键词：
Address Adjuvant Therapy Aerobic Affect Aftercare Animals Antineoplastic Agents Ascorbic Acid Biochemical Biology Buffers Cancer Patient Cancer cell line Cell Culture Techniques Cell Death Cell division Cells Characteristics Chemicals Coculture Techniques Culture Media DNA Damage Dose Drug Delivery Systems Elements Environment Epithelial Event Excision Exposure to Fibroblasts Fluorouracil Glutathione Glutathione Disulfide Goals Half-Life Heart Human Hydrogen Peroxide In Vitro Individual Intravenous Ionizing radiation Kinetics Lead Learning Life Maintenance Malignant Neoplasms Mediating Metals Methods Modeling NADP Normal Cell Normal tissue morphology Nutritional Organism Oxidation-Reduction Pathway interactions Pentosephosphate Pathway Peroxides Pharmaceutical Preparations Plasma Predisposition Prodrugs Production Property Reducing Agents Research Role Selectins System Testing Time Tissues Toxic effect aqueous ascorbate cancer cell cancer therapy chemical property extracellular gemcitabine improved in vivo neoplastic cell oxidation programs public health relevance response tumor tumor microenvironment

项目摘要

DESCRIPTION (provided by applicant): This research program will the investigate use of pharmacologic ascorbate (high-dose, i.v. delivery of vitamin C) in the treatment of cancer. Pharmacological ascorbate (AscH-) takes advantage of the basic chemical properties of AscH- to use it as a drug; in fact because of its properties as a reducing agent, pharmacologic AscH- is a pro-drug for the delivery of extracellular H2O2 to tumor cells. In this use of AscH-, it must be given intravenously; plasma levels of 20 - 30 mM are achieved; healthy individuals have plasma ascorbate levels on the order of 50 ?M (0.05 mM). With pharmacological AscH- the goal is to achieve a transient level of ascorbate in plasma on the order of 300-500 times that of typical healthy "nutritional" levels. The half-life of AscH- in plasma at these high levels is H2.3 h. Thus for 12 - 24 h after treatment, levels of AscH- in plasma greatly exceed healthy "nutritional" levels. We propose to investigate the mechanism of action of pharmacological AscH- to learn: (1) what biochemical properties make cancer cells susceptible to pharmacological AscH-; and (2) why it is not toxic to normal tissue. Our goal is to unravel basic biochemical mechanisms so this therapy can be employed in a broad range of appropriately selected cancers. We hypothesize that the difference in susceptibility of cells to pharmacological AscH- is the ability o maintain their intracellular redox buffer (GSSG,2H+/2GSH) at a half-cell reduction potential (Ehc) compatible with life. The rationale for this hypothesis is that: (1) AscH- readily autoxidize producing a flux of H2O2 (in cell culture media and in vivo); (2) the high levels of extra cellular AscH- achieved by i.v. delivery (H300-500X "nutritional" levels) produce a high flux of H2O2; (3) the removal of this high flux of H2O2 by cells results in a great demand for intracellular reducing equivalents, i.e. glutathione (GSH) and NADPH; (4) this results in oxidation of the intracellular redox buffer, leading to quiescence or cell death, depending on the extent of oxidation. Cells that maintain an appropriately reduced intracellular redox buffer will be less susceptible to exposure to pharmacological AscH-; cells that cannot maintain their intracellular redox buffer will die. Because the status of the redox buffer is maintained by the pentose phosphate pathway (PPP), we further propose that an oxidatively challenged redox buffer will be synergistic with agents that also connect to the PPP, e.g. gemcitabine, 5-fluorouricil, and especially ionizing radiation. This research program supports translational efforts by addressing the fundamental question of why pharmacological ascorbate is non-toxic to organisms, i.e. people, yet cancer cells can be very susceptible. The results of this study will guide translational efforts in selectng appropriate adjuvants for therapy and cancers (patients) that may benefit from this approach to treatment. 2

描述（由申请人提供）：该研究计划将研究药理学抗坏血酸（高剂量、静脉注射维生素 C）在癌症治疗中的用途。药理抗坏血酸（AscH-）利用AscH-的基本化学性质将其用作药物；事实上，由于其作为还原剂的特性，药理学 AscH- 是一种将细胞外 H2O2 递送至肿瘤细胞的前药。在使用 AscH- 时，必须静脉注射；血浆浓度达到 20 - 30 mM；健康个体的血浆抗坏血酸水平约为 50 µM (0.05 mM)。药理学 AscH- 的目标是使血浆中的抗坏血酸瞬时水平达到典型健康“营养”水平的 300-500 倍。在这些高水平下，血浆中 AscH- 的半衰期为 H2.3 小时。因此，治疗后 12 - 24 小时内，血浆中的 AscH- 水平大大超过健康的“营养”水平。我们建议研究药理学AscH-的作用机制，以了解：（1）哪些生化特性使癌细胞对药理学AscH-敏感； (2) 为什么它对正常组织没有毒性。我们的目标是揭示基本的生化机制，以便这种疗法可以应用于广泛的适当选择的癌症。我们假设细胞对药理学 AscH- 的敏感性差异在于将其细胞内氧化还原缓冲液 (GSSG,2H+/2GSH) 维持在与生命相容的半细胞还原电位 (Ehc) 的能力。这一假设的基本原理是：(1) AscH- 容易自氧化，产生大量 H2O2（在细胞培养基和体内）； (2)高水平的细胞外 AscH-通过静脉注射实现输送（H300-500X“营养”水平）产生高通量的H2O2； (3)细胞对这种高通量H2O2的去除导致对细胞内还原的巨大需求等价物，即谷胱甘肽 (GSH) 和 NADPH； (4) 这会导致细胞内氧化还原缓冲液氧化，导致细胞静止或死亡，具体取决于氧化程度。维持适当减少的细胞内氧化还原缓冲液的细胞将不太容易暴露于药理学 AscH-；无法维持细胞内氧化还原缓冲液的细胞将死。由于氧化还原缓冲液的状态是由磷酸戊糖途径（PPP）维持的，因此我们进一步提出，氧化挑战的氧化还原缓冲液将与也连接到PPP的试剂具有协同作用，例如吉西他滨、5-氟尿嘧啶，尤其是电离辐射。该研究计划通过解决为什么药理学抗坏血酸对生物体（即人类）无毒但癌细胞却非常敏感的基本问题来支持转化工作。这项研究的结果将指导转化工作，为治疗和可能受益于这种治疗方法的癌症（患者）选择合适的佐剂。 2