The metabolic adaptation evoked by arginine enhances the effect ofradiation in brain metastases
| Autor: | Maria Victoria Revuelta, Andrew Cho, Leandro Cerchietti, Kayvan R. Keshari, Rossella Marullo, M. Nieves Calvo-Vidal, Shao Ning Yang, Pablo Damian Cresta Morgado, Shira Yomtoubian, B. M. C. Roth, Monica Castro, Vanina Araceli Medina, Jan Krumsiek, Marcelo Bonomi, Alfredo Navigante, Vivek Mittal |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Multidisciplinary
biology Arginine Chemistry DNA damage Poly ADP ribose polymerase ARGININA SciAdv r-articles Life Sciences Nitric oxide chemistry.chemical_compound RADIACION CEREBRO Radioresistance Cancer cell METASTASIS biology.protein Cancer research Glycolysis Biomedicine and Life Sciences Glyceraldehyde 3-phosphate dehydrogenase Research Article Cancer TUMORES |
| Zdroj: | Science Advances Vol.7, No.45, 2021 Repositorio Institucional (UCA) Pontificia Universidad Católica Argentina instacron:UCA Science Advances |
| Popis: | Description Arginine enhances the effect of radiation in patients with brain metastasis by metabolic suppression of cancer cells. Selected patients with brain metastases (BM) are candidates for radiotherapy. A lactatogenic metabolism, common in BM, has been associated with radioresistance. We demonstrated that BM express nitric oxide (NO) synthase 2 and that administration of its substrate l-arginine decreases tumor lactate in BM patients. In a placebo-controlled trial, we showed that administration of l-arginine before each fraction enhanced the effect of radiation, improving the control of BM. Studies in preclinical models demonstrated that l-arginine radiosensitization is a NO-mediated mechanism secondary to the metabolic adaptation induced in cancer cells. We showed that the decrease in tumor lactate was a consequence of reduced glycolysis that also impacted ATP and NAD+ levels. These effects were associated with NO-dependent inhibition of GAPDH and hyperactivation of PARP upon nitrosative DNA damage. These metabolic changes ultimately impaired the repair of DNA damage induced by radiation in cancer cells while greatly sparing tumor-infiltrating lymphocytes. |
| Databáze: | OpenAIRE |
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