Background
Glioblastoma (GBM) is a tumor of the central nervous system. After surgical removal and standard therapy, recurrence of tumors is observed within 6–9 months because of the high migratory behavior and the infiltrative growth of cells. Here, we investigated whether carnosine (β-alanine-l-histidine), which has an inhibitory effect on glioblastoma proliferation, may on the opposite promote invasion as proposed by the so-called “go-or-grow concept”.
Methods
Cell viability of nine patient derived primary (isocitrate dehydrogenase wildtype; IDH1R132H non mutant) glioblastoma cell cultures and of eleven patient derived fibroblast cultures was determined by measuring ATP in cell lysates and dehydrogenase activity after incubation with 0, 50 or 75 mM carnosine for 48 h. Using the glioblastoma cell line T98G, patient derived glioblastoma cells and fibroblasts, a co-culture model was developed using 12 well plates and cloning rings, placing glioblastoma cells inside and fibroblasts outside the ring. After cultivation in the presence of carnosine, the number of colonies and the size of the tumor cell occupied area were determined.
Results
In 48 h single cultures of fibroblasts and tumor cells, 50 and 75 mM carnosine reduced ATP in cell lysates and dehydrogenase activity when compared to the corresponding untreated control cells. Co-culture experiments revealed that after 4 week exposure to carnosine the number of T98G tumor cell colonies within the fibroblast layer and the area occupied by tumor cells was reduced with increasing concentrations of carnosine. Although primary cultured tumor cells did not form colonies in the absence of carnosine, they were eliminated from the co-culture by cell death and did not build colonies under the influence of carnosine, whereas fibroblasts survived and were healthy.
Conclusions
Our results demonstrate that the anti-proliferative effect of carnosine is not accompanied by an induction of cell migration. Instead, the dipeptide is able to prevent colony formation and selectively eliminates tumor cells in a co-culture with fibroblasts.:1 Introduction ........................................................................2
1.1 Glioblastoma ........................................................................................................... 2
1.1.1 Taxonomy, epidemiology and general features of GBM ......................... 2
1.1.2 GBM subtypes and molecular diagnostic .................................................. 3
1.1.3 Therapy ........................................................................................................... 4
1.1.4 GBM cell migration and invasion ................................................................. 5
1.2 Carnosine ................................................................................................................ 6
1.2.1 Chemistry, Biology, Distribution .................................................................. 7
1.2.2 Carnosine homeostasis ................................................................................ 7
1.2.3 Physiological functions.................................................................................. 8
1.2.4 Therapeutic potential ..................................................................................... 9
1.2.5 Carnosine and cancer ................................................................................... 9
1.3 Objective of the study.......................................................................................... 10
2 Publication .......................................................................12
2.1 General information ............................................................................................. 12
2.2 Carnosine selectively inhibits migration of IDH-wildtype glioblastoma cells
in a co-culture model with fibroblasts ........................................................................... 13
3 Summary ..........................................................................23
4 References .......................................................................27
5 Appendix ..........................................................................34
5.1 Supplemental material ........................................................................................ 34
5.2 Author’s contribution............................................................................................ 36
5.3 Erklärung über die eigenständige Abfassung der Arbeit ............................... 37
5.4 Curriculum vitae ................................................................................................... 38
5.5 List of publications ............................................................................................... 39
5.6 Acknowledgements ............................................................................................. 41
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:35348 |
| Date | 12 September 2019 |
| Creators | Dietterle, Johannes Andreas |
| Contributors | Universität Leipzig |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:doctoralThesis, info:eu-repo/semantics/doctoralThesis, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
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