A p53/NFkB-mediated metabolic mechanism for chemotherapy protection

描述（申请人提供）：用于化疗保护的p53/NF κ B介导的代谢机制化疗仍然是当前的一线癌症治疗，但由此产生的严重副作用通常对癌症患者构成重大威胁，从而迫切需要开发用于化疗保护的有效策略。我们发现，低剂量砷预处理显着减轻化疗毒性，砷是通过诱导糖酵解。重要的是，砷介导的保护作用绝对 需要功能性的p53，使得有可能选择性地保护正常组织而不是癌细胞。使用肿瘤异种移植小鼠模型，我们证明了这种方法的有效性。我们假设p53介导的代谢重编程是化疗保护的一种新机制。我们将通过以下方式验证这一假设：1）将糖酵解和糖酵解酶与化疗保护直接联系起来; 2）探索负责细胞对化疗敏感性的代谢调节的机制; 3）研究p53介导的造血干细胞（HSC）代谢调节。当成功完成时，拟议的研究将揭示一种新的化疗保护代谢策略。重要性：化疗主要通过诱导DNA损伤来杀死癌细胞，DNA损伤也通过强烈激活p53而影响正常组织，导致病理后果。我们已经利用低剂量砷诱导的瞬时p53抑制来选择性地降低化疗药物在正常组织中的毒性。我们最近对荷瘤小鼠的研究为所提出的方法提供了原理证明。对p53/NFkB/HIF-1a轴介导的细胞和组织对化疗敏感性的代谢调节的拟议研究可能产生正常组织保护的新机制，这将使得能够开发减轻化疗毒性的新策略。我们在癌症研究的建议领域有着良好的记录，并且在开展概述的研究方面具有独特的优势。这项研究的总体目标是通过最大限度地减少不良副作用为癌症患者提供更有效的治疗，从而降低患者死亡率并提高生活质量。拟议的工作有可能从根本上影响癌症患者的护理。创新性：本提案的创新性在于我们研究的重点是化疗保护的代谢机制。我们的初步研究已经建立了几个在体外和体内的代谢标志物和测定，这是非常敏感的，应该使我们能够调查的机制，代谢途径调节细胞和组织的化疗敏感性。在低剂量砷介导的防御中，功能性p53的绝对需求及其与NF κ B/HIF-1a的拮抗相互作用为正常组织的选择性保护提供了良好的基础。染色质修饰的代谢调节代表了化疗保护的新机制。糖酵解介导的HSC适应性和应激耐受性可能为保护HSC免受化疗毒性提供新的方法。

DESCRIPTION (provided by applicant): A p53/NFkB-mediated metabolic mechanism for chemotherapy protection Chemotherapy remains the current front line cancer treatment, but the resulting severe side effects often pose a significant threat to cancer patients, raising a pressin need for the development of effective strategies for chemotherapy protection. We found that low-dose arsenic pretreatment markedly alleviates the chemotherapy toxicity, and that arsenic does so via induction of glycolysis. Of significance is that arsenic-mediated protection absolutely requires functional p53, making it possible to selectively protect only normal tissues but not cancer cells. Using tumor xenograft mouse models, we demonstrated the effectiveness of this approach. We hypothesize that the p53-mediated metabolic reprogramming is a novel mechanism of chemotherapy protection. We'll test the hypothesis by; 1) directly linking glycolysis and glycolytic enzymes to chemotherapy protection; 2) exploring the mechanisms responsible for metabolic regulation of cellular sensitivity to chemotherapy, 3) investigating p53-mediated metabolic regulation of hematopoietic stem cells (HSC). When successfully completed, the proposed studies would uncover a novel metabolic strategy for chemotherapy protection. Significance: Chemotherapy kill cancer cells primarily via induction of DNA damage, which also affects normal tissues by strongly activating p53 causing pathological consequences. We have exploited low-dose arsenic-induced transient p53 inhibition to selectively reduce chemotherapeutics toxicity in normal tissues. Our recent studies with tumor-bearing mice have provided proof-of-principle for the proposed approach. The proposed investigation into the p53/NFkB/HIF-1a axis- mediated metabolic regulation of cell and tissue sensitivity to chemotherapy may yield a new mechanism of normal tissue protection, which would enable the development of novel strategies to alleviate chemotherapy toxicity. We have a proven record in the proposed areas of cancer research and are uniquely positioned to carry out the outlined studies. The overarching goal of this research is to provide more effective treatment for cancer patients by minimizing adverse side effects and thereby to reduce patient mortality and to improve quality of life. The proposed work has potential to impact cancer patient care in a fundamental way. Innovation: The innovative nature of this proposal lies in the focus of our study on the metabolic mechanism of chemotherapy protection. Our preliminary studies have established several in vitro and in vivo metabolic markers and assays, which are exquisitely sensitive and should enable us to investigate mechanisms by which metabolic pathways regulate cellular and tissue sensitivity to chemotherapy. The absolute requirement of functional p53 and its antagonistic interaction with NFkB/HIF-1a in low-dose arsenic-mediated defense provides a sound foundation for selective protection to normal tissues. The metabolic regulation of chromatin modification represents a novel mechanism of chemotherapy protection. The glycolysis-mediated fitness and stress tolerance of HSCs may offer a new method of protecting HSCs from chemotherapy toxicity.