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

• 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
• 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

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）：该研究计划将调查使用药物抗坏血酸（高剂量，i.v.递送维生素C）在癌症治疗中的使用。药理学抗坏血酸（ASCH-）利用ASCH-将其用作药物的基本化学特性；实际上，由于其作为还原剂的特性，药理学ASCH-是将细胞外H2O2递送至肿瘤细胞的促毒物。在这种ASCH-的使用中，必须静脉注射；血浆水平为20-30毫米；健康个体的血浆抗坏血酸水平为50？m（0.05 mm）。使用药理学ASCH-目标是达到血浆中抗坏血酸的瞬态水平，其量约为300-500倍的典型健康“营养”水平。在这些高水平的血浆中，Asch-的半衰期为H2.3 h。因此，治疗后12-24小时，血浆中的ASCH水平大大超过了健康的“营养”水平。我们建议研究药理学ASCH-学习的作用机理：（1）哪种生化特性使癌细胞易受药理学ASCH-的影响； （2）为什么它对正常组织无毒。我们的目标是阐明基本的生化机制，以便可以在适当选择的癌症中采用这种疗法。 我们假设细胞对药理学ASCH-的敏感性的差异是o保持其细胞内氧化还原缓冲液（GSSG，2H+/2GSH）的能力，以半细胞还原电位（EHC）兼容。该假设的理由是：（1）ASCH-易于自氧化产生H2O2的通量（在细胞培养基和体内）； （2）高水平的额外细胞 i.v.实现的asch递送（H300-500X“营养”水平）产生H2O2的高通量； （3）通过细胞消除H2O2的高通量导致细胞内还原的需求 等效物，即谷胱甘肽（GSH）和NADPH； （4）这导致细胞内氧化还原缓冲液的氧化，根据氧化程度，导致静止或细胞死亡。保持适当减少的细胞内氧化还原缓冲液的细胞将不易暴露于药理学ASCH-；无法维持其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五磷酸五磷酸途径（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与PPP连接的药物保持协同作用，例如吉西他滨，5-氟尿质，尤其是电离辐射。 该研究计划通过解决了为什么药理抗坏血酸对生物无毒的基本问题，即人，即人，而癌细胞可能非常容易受到影响。这项研究的结果将指导在选择适当的治疗佐剂和癌症（患者）中的转化工作，这些佐剂可能受益于这种治疗方法。 2