Co-application of canavanine and irradiation uncouples anticancer potential of arginine deprivation from citrulline availability
| Autor: | Leoni A. Kunz-Schughart, Oleg Chen, F. Manig, Sebastian R. Merker, Daniel E. Stange, Oleh V. Stasyk, Yaroslav Bobak, Philipp Grosse-Gehling, Thomas Henle, Yuliya Kurlishchuk, Steffen Löck, Bozhena Vynnytska-Myronovska |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
normal colon organoids Cell cycle checkpoint Arginine ASS1 expression Colorectal cancer Argininosuccinate synthase Cell Gene Expression Apoptosis Argininosuccinate Synthase Radiation Tolerance colorectal cancer (CRC) 03 medical and health sciences chemistry.chemical_compound Canavanine Cell Line Tumor Radiation Ionizing Spheroids Cellular medicine Citrulline Tumor Cells Cultured Humans Intestinal Mucosa arginine deprivation 030102 biochemistry & molecular biology biology business.industry Cell Cycle DNA Methylation medicine.disease medicine.anatomical_structure Oncology chemistry Immunology biology.protein Cancer research CRC spheroids business Colorectal Neoplasms Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Yuliya Kurlishchuk 1, 2 , Bozhena Vynnytska-Myronovska 1, 2, 6 , Philipp Grosse-Gehling 1 , Yaroslav Bobak 2 , Friederike Manig 1, 3 , Oleg Chen 1, 2 , Sebastian R. Merker 4 , Thomas Henle 3 , Steffen Lock 1 , Daniel E. Stange 4 , Oleh Stasyk 2 , Leoni A. Kunz-Schughart 1, 5 1 OncoRay–National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, TU Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology, Dresden, Germany 2 Department of Cell Signaling, Institute of Cell Biology, National Academy of Sciences of Ukraine, Lviv, Ukraine 3 Institute of Food Chemistry, TU Dresden, Dresden, Germany 4 Department of Gastrointestinal, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany 5 Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford, UK 6 Current address: Clinic of Urology and Pediatric Urology, Saarland University Medical Center, Homburg/Saar, Germany Correspondence to: Leoni A. Kunz-Schughart, email: leoni.kunz-schughart@oncoray.de Keywords: arginine deprivation, ASS1 expression, colorectal cancer (CRC), CRC spheroids, normal colon organoids Received: January 27, 2016 Accepted: September 19, 2016 Published: September 28, 2016 ABSTRACT The moderate anticancer effect of arginine deprivation in clinical trials has been linked to an induced argininosuccinate synthetase (ASS1) expression in initially ASS1-negative tumors, and ASS1-positive cancers are anticipated as non-responders. Our previous studies indicated that arginine deprivation and low doses of the natural arginine analog canavanine can enhance radioresponse. However, the efficacy of the proposed combination in the presence of extracellular citrulline, the substrate for arginine synthesis by ASS1, remains to be elucidated, in particular for malignant cells with positive and/or inducible ASS1 as in colorectal cancer (CRC). Here, the physiological citrulline concentration of 0.05 mM was insufficient to overcome cell cycle arrest and radiosensitization triggered by arginine deficiency. Hyperphysiological citrulline (0.4 mM) did not entirely compensate for the absence of arginine and significantly decelerated cell cycling. Similar levels of canavanine-induced apoptosis were detected in the absence of arginine regardless of citrulline supplementation both in 2-D and advanced 3-D assays, while normal colon epithelial cells in organoid/colonosphere culture were unaffected. Notably, canavanine tremendously enhanced radiosensitivity of arginine-starved 3-D CRC spheroids even in the presence of hyperphysiological citrulline. We conclude that the novel combinatorial targeting strategy of metabolic-chemo-radiotherapy has great potential for the treatment of malignancies with inducible ASS1 expression. |
| Databáze: | OpenAIRE |
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