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.
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 patient care in a fundamental way.
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