- REAL-TIME MONITORING OF IN VIVO FREE RADICAL SCAVENGERS THROUGH HYPERPOLARIZED N-ACETYL CYSTEINE ISOTOPES
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A method of diagnosing or monitoring a patient suffering from cancer, the method comprising: administering a pharmaceutical composition comprising an effective amount of an active agent, wherein the active agent is [1-13C] N-acetyl cysteine, a deuterated derivative thereof, a pharmaceutically acceptable salt of any of the foregoing thereof, or a combination thereof, together with a pharmaceutically acceptable carrier to the patient; and diagnosing or monitoring the patient by hyperpolarized 13C-MRI. Also disclosed is a method of synthesizing [1-13C] N-acetyl cysteine or a deuterated derivative thereof.
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Paragraph 0151-0152
(2021/07/24)
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- Cysteine dioxygenase 1 is a metabolic liability for non-small cell lung cancer
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NRF2 is emerging as a major regulator of cellular metabolism. However, most studies have been performed in cancer cells, where co-occurring mutations and tumor selective pressures complicate the influence of NRF2 on metabolism. Here we use genetically engineered, non-transformed primary murine cells to isolate the most immediate effects of NRF2 on cellular metabolism. We find that NRF2 promotes the accumulation of intracellular cysteine and engages the cysteine homeostatic control mechanism mediated by cysteine dioxygenase 1 (CDO1), which catalyzes the irreversible metabolism of cysteine to cysteine sulfinic acid (CSA). Notably, CDO1 is preferentially silenced by promoter methylation in human non-small cell lung cancers (NSCLC) harboring mutations in KEAP1, the negative regulator of NRF2. CDO1 silencing promotes proliferation of NSCLC by limiting the futile metabolism of cysteine to the wasteful and toxic byproducts CSA and sulfite (SO3 2-), and depletion of cellular NADPH. Thus, CDO1 is a metabolic liability for NSCLC cells with high intracellular cysteine, particularly NRF2/KEAP1 mutant cells.
- Kang, Yun Pyo,Torrente, Laura,Falzone, Aimee,Elkins, Cody M.,Liu, Min,Asara, John M.,Dibble, Christian C.,Denicola, Gina M.
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